Professional Documents
Culture Documents
MORPHINE ALKALOIDS
BY
K. W. B E N T L E Y
IiECTTrREB I N O H B M I S T E Y I N T H E
TTNIVBESITY OJ- A B B E D E E N
OXFORD
AT THE CLARENDON PRESS
1954
Oxford University Press, Amen House, London E.G. 4
GLASGOW NEW YOEK TOEONTO MELBOUENE WELLINGTON
BOMBAY OALOTJTTA MADBAS KABACHI OAPE TOWN IBADAN
P R I N T E D I N GBBAT BRITAIN/
FOREWORD
I N 1932 the U.S. Treasury Department (Public Health Service) pub-
lished an excellent monograph, Chemistry of the Opium Alkaloids, by-
Professor Lyndon F . Small assisted by Associate Professor Robert E.
Lutz.
The progress made in the last two decades has been so great, however,
t h a t a new work is required. This is all the more timely in t h a t the
formal synthesis of morphine by Professor M. Gates and his co-workers
has finally established the validity of the constitutional formula pro-
posed b y Gulland and the writer in 1925.
The second volume of The Alkaloids (Academic Press) by R. H. F .
Manske and H . L. Holmes, which contains three long chapters on
morphine, thebaine, and sinomenine, appeared in 1952 whilst the present
work was in preparation. The apparent duplication is not regretted
partly on account of the new matter which it is now possible to include
and partly because of the misunderstanding of the stages of develop-
ment of the structural theory which does not show in true perspective
some points where English chemists made a significant contribution.
Holmes (loc. cit., p . 26) remarks that the modern formulae (meaning
our own) are but a small modification of those of Knorr and are based on
Knorr's results together with a small further piece of evidence.
Again (p. 27) he states t h a t Knorr's formula explained satisfactorily
the complex rearrangements of morphine and thebaine. The first state-
ment is misleading and the second will be seen to be incorrect on inspec-
tion of the details. For example, Knorr-codeinone to thebenine demands
either a migration of carbonyl, or of the ethanamine chain, which cannot
be theoretically justified, or based on analogy in any simple manner.
We allow no one to surpass us in respect for Knorr and Pschorr and
other pioneers of morphine chemistry. They established the main facts,
especially the constitutions of the phenanthrene degradation products,
including morphenol and thebaol, and the very important transforma-
tion products thebenine, morphothebaine, and apomorphine. But until
1925 there was no consistent explanation of these degradations and
transformations in terms of any acceptable structures for the parent
bases. W h a t appears to be a very small change in structure involved
very great changes in the interpretations, and in fact proved the small
key that unlocked a particularly massive door.
This is perhaps a suitable opportunity to recall the circumstances at
t h a t juncture, but in doing so it is far from the writer's wish to imply
any comparison of the relative value of the key and the door.
I n considering this stage of the development it is not difficult to
oonfuBe the issue by unduly metioulous attention to the formulae in
Vl FOREWORD
which codeine is represented as unsaturated, ignoring at the same time
the equivalence of a bridged-ring structure for certain purposes.
Thus the allylic rearrangement of codeine to pseudocodeine was
virtually recognized for the first time by Gulland and the writer in 1923.
The swing of a bridge took the place of that of a bond. In that paper
of 1923 the analogy of the process to the geraniol-linalol transformation
was specifically indicated.
In 1925 we were sure that codeine is unsaturated, partly because we
had made it into a glycerol by the action of very dilute potassium
permanganate.
And in that year Wieland and Kotake, and Gulland and Robinson,
simultaneously and independently, ascribed the correct positions of
wc-hydroxyl and double bond to codeine (isocodeine) (i) and pseudo-
codeine (allopseudocodeine) (n). The existence of the oxide ring shown
in these formulae had long been established.
[IV] LV]
The position attributed to the oxygen was based on the conviction
that a carbonyl oxygen (in codeinone and pseudocodeinone) would
not migrate. Hence Pschorr's syntheses of 3:4:6-trimethoxyphenan-
throno, obtainable from codeinone, and 3:4:8-trimethoxyphenanthrene,
obtainable from pseudocodeinone, fixed the positions of the carbonyl
group of tho ketones, and therefore those of the sec-alcoholic groups of
oodeino and pseudocodeine also.
This led at onoo to tho bis-othenoid system of a-codoimethine (in)
and /3-oodoimothino (iv).
A year lator van J)uin, RobinBon, and Smith found that noopino (q.v.)
is /3-codoino (v) and is directly convertible into jS-oodoimotliino. [i to v
inoluslvo arc parts of tho full structures,]
FOREWORD vii
The appearance of a double bond in the 9:10 position during the
formation of a-codeimethine was consistent with the attachment of the
basic nitrogen to one of these carbon atoms. Position 9 was generally
preferred by the early theorists, probably on conscious or subconscious
biogenetic grounds, in t h a t the other opium alkaloids are /3-arylethyl-
amine derivatives.
We selected position 9 not only on the basis of the structural relation
with tsoquinoline alkaloids, but also because it was the only position t h a t
allowed us to give an explanation of the formation of thebenine (vi) from
codeinone (VII).
MeO
CH2
CHO
MeNH-CH2-CH1 CH2CH2-NHMe
OH 0=
[VI] [VII] [VIII]
McO
[IX] [XI]
HO HO
CH2 CH2
CH- - N H CH
o>H-
^NH
CH2 i
HO
[XII] [XIII]
R. R O B I N S O N
III. PSEUDOMORPHINE 51
V. PORPHYROXINE 98
IX. T H E D E S O X Y C O D E I N E S A N D T H E I R D E R I V A T I V E S 149
XII. T H E R E D U C T I O N OF T H E B A I N E 197
BAINE 204
Experientia, Experientia.
Farmatisiya, Farmatisiya.
Farm. Nueva, Farmacia Nueva (Madrid).
Farm. Zhur., Farmatsevtichnii Zhurnal.
Frdl., Friedlaender, Fortschritte der Teerfarben-fabrikation.
French Pat., French Patent.
Oazz. Ohim. Hal., Gazzetta Chimica ItaKana.
Gilbert's Ann. der Physik, Gilbert's Annalen der Physik.
Hanb. Krist.-Phys. Chem., Handbuch der kristall-physikalisehen Chemie.
HeIv. Ohim. Acta, Helvetica Chimica Acta.
Ind. Eng. Chem. (Anal. Edn.), Industrial and Engineering Chemistry (Analytical
Edition).
Indian J. Med. Pes., Indian Journal of Medical Research.
Industria Chimica, Industria Chimica.
J.A.G.8., Journal of the American Chemical Society.
J. Agr. Soc. Japan, Journal of the Agricultural Society of Japan.
Jahresber. Chem., Jahresbericht der Chemie.
Jahresber. Chem. Tech., Jahresbericht der chemisch-technischen Reichsanstalt.
Leipzig.
Jahresber. Fortschr. Chem., Jahresbericht uber die Fortschritte der Chemie.
Jahresber. Fortschr. Phys. Wiss., Jahresbericht uber die Fortschritte der physischen
Wissenschaften.
Jahresber. Pharm., Jahresbericht der Pharmazie.
J. Am. Pharm. Assoc, Journal of the American Pharmaceutical Association.
J. Applied Chem. U.S.S.R., Journal of Applied Chemistry of U.S.S.R.
J. Assoc. Official Agr. Chem., Journal of the Association of Official Agricultural
Chemists.
J. Biol. Chem., Journal of Biological Chemistry.
J. Chem. Ind. U.S.S.R., Journal of Chemical Industry of TJ.S.S.R.
J. Chem. Phys., Journal of Chemical Physics.
J. Chem. Soc. Japan, Journal of the Chemical Society of Japan.
J. CMm. Med., Journal de Chimie Medicale.
J.C.S., Journal of the Chemical Society (London).
J. Cen. Chem. U.S.8.P., Journal of General Chemistry, TJ.S.S.R.
J. Indian Chem. Soc, Journal of the Indian Chemical Society.
J . Lab. Clin. Med., Journal of Laboratory and Clinical Medicine.
J. Org. Chem., Journal of Organic Chemistry.
J. Pharm., Journal de Pharmacie.
J. Pharm. BeIg., Journal de Pharmacie de Belgique.
./. Pharm. Chim., Journal de Pharmacie et de Chimie.
J. Pharm. Elsass Lothr., Journal der Pharmazie von Elsass-Lothringen (MuI-
hausen).
J. Pharm. Pharmacol., Journal of Pharmacy and Pharmacology.
J. Pharm. Soc. Japan, Journal of the Pharmaceutical Society of Japan.
J. Phys. Chem., Journal of Physical Chemistry.
J. pr. Chem., Journal fur praktische Chemie.
J. Soo. Chem. Ind., Journal of the Society of Chemical Industry.
J. Wash. Acad. ScL, Journal of the Washington Academy of Sciences.
XVlU ABBREVIATIONS
Khim. Farm. Prom., Khimiko-Farmatsevticheskya Promyshlennost'.
Khim. Beferat. Zhur., Khimicheskii Referativnyi Zhurnal.
Landwirtschafil. Versuchsstationen, Die landwirtschaftlichen Versuchsstationen.
L'Orosi, L'Orosi, Bollettino di chimioa farmaoia e soienze affini.
Maanblad voor Naturwettenschappen (Amsterdam), Maanblad voor Naturwetten-
sohappen (Amsterdam).
Mem. Proo. Manchester Lit. Phil. Soe., Memoirs and Proceedings of the Man-
chester Literary and Philosophical Society.
Mikrochemie, Mikrochemie.
Monatsh., Monatshefte fur Chemie und verwandte Teile anderer Wissenschaften.
Mori. Prod. Chim., Moniteur des Produits Chimiques.
Munch. Med. Wochschr., Miinchener medizinische Wochenschrift.
Nature, Nature.
Naturwiss., Naturwissenschaften.
Natuurw. Tijdschr., Natuurwettenschappelijk Tijdschrift.
Org. Ghem. Ind. U.S.S.B., The Organic Chemical Industry (U.S.S.R.).
Pharm. Acta HeIv., Pharmaceutica Acta Helvetiae.
Pharm. J. Trans., The Pharmaceutical Journal and Transactions.
Pharm. Monatsh., Pharmazeutische Monatshefte.
Pharm. Post, Pharmazeutische Post.
Pharm. Weekblad, Pharmazeutische Weekblad.
Pharm. Zentralhalle, Pharmazeutische Zentralhalle.
Pharm. Ztg., Pharmazeutische Zeitung.
Phil. Trans. Boy. Soc, Philosophical Transactions of the Royal Society.
Pogg. Ann. der Physik, Poggendorff's Annalen der Physik.
Proc. Ohem. Soc, Proceedings of the Chemical Society.
Proc. Imp. Acad. (Tokyo), Proceedings of the Imperial Academy (Tokyo).
Proc. Ind. Acad. Sci., Proceedings of the Indian Academy of Science.
Proc. Jap. Pharmacol. Soc, Proceedings of the Japanese Pharmacological Society.
Proc. Soc. Exptl. Biol. Med., Proceedings of the Society for Experimental Biology
and Medicine.
Quart. J. Pharm. Pharmacol., Quarterly Journal of Pharmacy and Pharmacology.
Quim. e ind., Quimica e industria.
Itec. Trav. Chim., Recueil des Travaux Chimiques des Pays-Bas.
Bept. Inst. Sci. Bes. Manchouhuo, Report of the Institute of Scientific Research,
Manchoukuo.
Bcv. Facultd Sci. Univ. Istanbul, Revue de la Faculte des Sciences de l'TJniversite
d'Istanbul.
Buss. Pat., Russian Patent.
Sohweiz. Apoth.-Ztg., Schweizerische Apotheker-Zeitung.
Schweiz. Wochschr., Schweizerische Wochenschrift.
Science, Scionco.
Science and Culture, Scionco and Culture.
Sei. Repts. Natl. Tsinghau Univ., Science Roports of tho National Tsinghau
UnivorHily.
Semnna Mid. (Buenos Airna), Ln Somalia M6dioa (HUOHOH Airos).
Sitzber.Ahml. lyMS.Witw.HitwinRBbnviolitoclOTAkadoniiodia'Wi^onsoliaflon.Wion.
SUddmU. Apoth.-Ztg., Hllddoutnoho Apobhtikor-ZtilUjng.
ABBREVIATIONS XlX
OH
[IX] [X] [XI] [XII]
Meanwhile several other formulae for morphine had been suggested,
namely:
(a) I x n ] by Vis [33] on the groundless assertion that phenanthrene is
only formed during the zinc-dust distillation of morphine by a
4 INTKODUCTION OH. I
represented as involving a shift of the double bond from the 8:14 to the
13:14 position, though /3-codeimethine does not behave on hydrogena-
tion as a fully aromatic naphthalene derivative. Faltis [60] also pro-
posed a 9:5 bridge structure for morphine [xxv] during speculations
on the biogenesis of the alkaloids.
thebenine [xxin] by hot dilute hydrochloric acid [56]; but against such
a formula may be cited the ready hydrogenation of thebaine [66-68]
and codeine [69-70], the hydrolysis of dihydrothebaine to dihydrocodei-
none [66], and the production of thebaizone, which is the methyl ester
of an aldehydic acid, on ozonolysis of thebaine [71-72].
In 1923 Gulland and Robinson [82] made a new survey of the evi-
dence for the constitution of the morphine alkaloids and came to the
following conclusions. The most striking and unique property of the
morphine alkaloids is their tendency to lose the whole of the ethanamine
side-chain during degradation, giving phenanthrene derivatives; it is
obvious that this property is due to some peculiarity of the molecule
and any adequate formula must be capable of explaining it. 'The
driving force behind the change is doubtless the tendency to produce an
aromatic nucleus, because extrusion of the side-chain is never observed
independently of the formation of an aromatic phenanthrene system.
The formation of the aromatic phenanthrene derivative cannot take place
for structural reasons unless the ethanamine side-chain is displaced in
favour of a hydrogen atom or a hydroxyl group.'
On these grounds they proposed attachment of the oarbon end of the
side-chain at an angular position so that its oxtrusion is a necessary
part of aromatization, and of the two available positions, 1IJ and 14,
tho former was eolootod, Those suggestions wore embodied in the
CH. I INTRODUCTION 9
modified camphane formulae [XLI] and [XLII] for morphine and thebaine
respectively, as codeine was believed not to contain a double bond.
[LII] [LIII]
Schopf sought to obtain direct evidence for the location of the side-
chain at C-13 by subjecting dihydrocodeinone oxime to a Beckmann
transformation, when, if the side-chain is located at C-13 [LIV], an
aldehyde [LV] would be the product, whereas if the point of attachment
is C-14 [LVI] a ketone [LVII] would be formed. Neither the oxime nor
its methyl ether yielded the desired proof directly, and it was only after
a sequence of further degradations t h a t the conclusion was drawn t h a t
the product was [LV], indicating C-13 as the point of attachment of the
side-chain [85] (see Chap. X).
Further work by Schopf and Borkowsky [86] indicated the need for
modification of the structure with attachment of the side-chain at C-14
in metathebainone [LVIII], which is formed by the reduction of thebaine
with stannous chloride in concentrated hydrochloric acid [27]. The true
thebainono [LIX] was later isolated from the stannous chloride reduction
xmder difforont conditions. Metathebainone arises as a result of re-
arrangement of thebaine in concentrated hydrochloric acid, now
boliovod to involve tho intermediate [LX], which is also believed to be
oomraon to tho morpholhobaino and thobonino transformations [88-
HOJ. (Hoo Olntp. XXV.)
CH. I INTRODUCTION 11
One alternative formula can be envisaged and this can best be ex-
plained by reference to the intermediate [LX] postulated in the complex
rearrangements t h a t thebaine undergoes in acid solution, [LX] arises
from [XLVI] by migration of the side-chain from 13 to 14 and hydrolysis;
it could equally well arise from [ L X I I I ] . The only way of distinguishing
between [XLVI] and [LXIII] appears to be by a study of the ultra-violet
absorption spectra of a- and /J-codeimethines, which strongly support
[XLVI], the spectrum of/3-codeimethine clearly showing the conjugation
of two double bonds with the aromatio nuolous [88-89]. These results
12 INTRODUCTION OH. I
MeO
HO'
Recently the alkaloid oripavine has been shown to have the structure
[LXVI] and bears the same relationship to morphine as thebaine does t o
codeine. On methylation with diazomethane it yields thebaine [96].
Sinomenine, discovered by Ishiwari in Sinomenium diversifolius [97],
has been shown by the researches of Kondo [98] and particularly of Goto
and his co-workers [99-100] to have the structure [LXVII] and to be the
optical antipode of 7-methoxythebainone. I t is readily converted into
antipodes of substances obtainable from thebaine and codeine (see
Chap. XXVI). Hasubanonine, an alkaloid isolated from Stephania
japonica, is believed to be of the morphine type [101] (see Chap. X X V I ) .
BIBLIOGRAPHY TO C H A P T E R I
1. SEBTUBNEB, Trommsdorff's Journal 11. P E I X E T I E B , J. Pharm., 1835, (2), 2 1 ,
der Pharmazie, 1805, (1), 13, 234. 555.
2. CHASTAING, J. Pharm., 1881, (5), 4, 91. 12. KNOBB, and H O R L E I N , Ber., 1906, 39,
3. ROBIQUET, Ann. Chim. Phys., 1832, 1409.
(2), 5 1 , 225. 13. VONGEBICHTEN, ibid., 1897, 30, 354.
4. GBIMAUX, Cornpt. Rend., 1881, 92, 14. GBIMAUX, Compt. Rend., 1881,93, 591.
1140. 15. VONGEBICHTEN and SOHBOTTEB, Ber.,
6. ibid. 1228. 1882, 15, 1484.
6. WmaiiT, J.O.S., 3 874, 1031. 16. F I S O H E B and VONGKBIOHTEN, ibid.,
7. HfflSSffl, Ann., 1883,222, 203. 1886, 19, 792.
8. VoNamuoiiTJUN-, ibid., 1881, 210,1OB. 17. PtIBtTND and OOiraij, ibid., 1895, 2 8 ,
0. So raw vim ami LIOIOH, J.O.R., JO(K), OdI.
1024, 1H. VrwciiniuajiTiiw and SairnOTTnm, Ann.,
10. Aan mid K N O M I , 3hr 1 l)0!l, 36, 007. IHHI, 210, 3I)(S.
OH. I INTRODUCTION 13
19. K N O B B , Ber., 1889,22, 1113. 62. V O N B B A U N a n d CASS, Ann., 1927,451,
20. ibid., 1899, 32, 742. 55.
21. PSOHOBB and SITMULEANIT, ibid., 1900, 63. E B E U N D , M B L B E B , and SCHLESINGEE,
33, 1810. J. pr. CUm., 1920 (2), 101, 1.
22. VONGBBIOHTEN, ibid., 1902,35, 4410. 64. and S P E Y E B , Ber., 1916,49,1287.
23. K N O B B , ibid., 1903, 36, 3074. 65. H O W A B D , ibid., 1884, 17, 527.
24. PSOHOBB, S E Y D E L , a n d S T O H B E B , ibid., 66. F B E U N D , SPEYEB, and GOTTMANN,
1902, 3 5 , 4400. ibid., 1920, 5 3 , 2250.
25. K N O B B , ibid., 1904, 37, 3499. 67. SKITA, N O B D , R E I C H E B T , a n d S T U -
26. and H O B L E I N , ibid., 1907, 40, KAET, ibid., 1921, 54, 1560.
2032. 68. W I E L A N D a n d K O T A K E , Ann., 1925,
27. PSOHOBB, P F A P P , and HEBSCHMANN, 444, 69.
ibid., 1905, 38, 3160. 69. SKITA a n d FBANOK, Ber., 1911, 44,
28. K N O B B and PSOHOBB, ibid. 3172. 2862.
29. ibid. 3143. 70. OLDENBEBG, D. B.-P., 260,233 (1911);
30. ibid., 1889, 22, 181. Frdl., 11, 996; Houben, 4, 58.
31. VONGEEICHTEN a n d D I T T M E B , ibid., 71. P S O H O B B and E I N B E C K , Ber., 1907,40,
1906, 39, 1718. 3652.
32. P S O H O B B , Ann., 1912, 391, 40. 72. W I E L A N D and SMALL, Ann., 1928,
33. Vis, J. pr. CUm., 1893 (2), 47, 584. 467, 17.
34. K N O B B , Ber., 1894, 27, 1144, note 2. 73. FALTIS, Arch. Pharm., 1917, 255, 85.
35. VONGBBIOHTEN, ibid., 1900, 3 3 , 352. 74. and STTPPAN, Pharm. Monatsh.,
36. F B E U N D , ibid., 1905, 38, 3234. 1923, 4, 189.
37. BUOHEEEB, Z. angew. Ghem., 1907,20, 75. Monatsh., 1922, 4 3 , 382.
1672. 76. GADAMEB, Z. angew. CUm., 1913, 2 6 ,
38. OUm. Ztg., 1907, 3 1 , 921. 625.
39. J. pr. CUm., 1907 (2), 76, 428. 77. W I E L A N D and K A P P E L M E I E B , Ann.,
40. K N O B B and SOHNEIDEB, Ber., 1906, 1911,382, 306.
39, 1414. 78. and KOBALECK, ibid., 1923, 4 3 3 ,
41. and H 6 B L E I N , ibid., 1907, 4 0 , 267.
2042. 79. STBATJSS and E H B E N S T E I N , ibid., 1925,
42. PSOHOBB and E I N B E C K , ibid. 1980. 442, 93.
43. MATTHIESSEN a n d W E I G H T , Proc. Hoy. 80. Z I E G L E B , ibid., 4 4 3 , 161.
Soc, 1869, 17, 455. 81. W I E L A N D and GABBSCH, Ber., 1926,
44. Ann. Suppl., 1870, 7, 170. 59, 2490.
45. PSOHOBB and K A R O , Ber., 1906, 3 9 , 82. GULLAND and ROBINSON, J.C.S.,
3124. 1923, 980.
46. J A E C K E L , and F E C H T , ibid., 1902, 83. Mem. Proc. Manchester Lit.
35, 4377. Phil. Soc, 1925, 69, 79.
47. EINBECK, and SPANGENBEBG, 84. CAHNandRoBiNSON.J.C.S., 1926,908.
ibid., 1907, 40, 1998. 85. ScHOPir, Ann., 1927, 452, 411.
48. a n d BUSCH, ibid. 2001. 86. and BOBKOWSKY, ibid., 458, 148.
49. ibid. 1984. 87. and H I E S C H , ibid., 1931,489, 224.
50. L E E S , J.C.S., 1907, 1408. 88. ROBINSON, Proc. Boy. Soc, 1947,
Cl. K N O B B and H O B L E I N , Ber., 1907, 4 0 , 135B, v-xix.
4883. 89. . Nature, 1947, 160, 815.
52. ibid., 1908, 4 1 , 969. 90. SANDEBMAN, Ber., 1938, 7 1 , 648.
G3. ibid., 1906,39, 4409. 91. SCHOPT, VON GOTTBEBG, and P E T E I ,
54. ibid., 1907,40, 4889. Ann., 1938, 536, 216.
55. ibid. 3341. 92. SMALL, SABGENT, and BBALLEY, J.
56. H E S S E , Ann., 1870, 153, 47. Org. Ohem., 1947, 12, 847.
57. F B E E N D , Ber., 1894, 2 7 , 2961. 93. B E N T L E Y and ROBINSON, J.C.S., 1952,
58. MICHAELS, a n d GOBEL, ibid., 947.
1897, 30, 1357. 94. G B E W E , MONDON, and N O L T E , Ann.,
59. PSOHOBB a n d MASSAOITT, ibid., 1904, 1949, 564, 161.
37, 2780. 95. GATES and T S C H O T I , J.A.C.S., 1950,
00. FALTIS, Pharm. Post, 1907,39,497 and 72, 4839.
500. 00. KONOVALOVA and KISELTW, . / . Oan.
01. VON BKAUK, Bur,, 1OU, 47, 2312. CUm. U.S.SJL, 1048, 18, 855.
14 INTRODUCTION OH. I
97. ISHIWARI, Chugai Iji Shvmpo, 1920, 100. GOTO et al., Bull. Ohem. Soc. Japan,
959, 1. 1929, 4, 163, 103, 195, 244; 1930,
98. K O N D O and OCHIAI, Ann., 1929, 470, 5, 93, 311, 315; 1931, 6, 79, 126,
224. 197, etc.
99. GOTO, Proa. Imp. Acad. [Tokyo), 1926, 101. K O N D O , SATOMI, and ODERA, Ann.
2, 7, 167 a n d 414. Rep. Itsuu Lab., 1951, 2, 33.
II
M O R P H I N E AND ITS I S O M E R S
MORPHINE
M O R P H I N E was the first vegetable base to be isolated and recognized
as such, the isolation from opium being first described by Sertiirner in
1805 [1] and later years [2-7] (Serturner's papers relating to morphine
have since been reprinted [8]), though as pointed out by Pelletier [9]
Seguin described the preparation of the base in 1804 in a report to the
Academy of Sciences that was not published until 1814 [10]. The alka-
loid was also isolated by Robiquet in 1817 [11-12]. I n 1803 Derosne, by
extracting opium with water and precipitating the extract with potas-
Hium carbonate, obtained an apparently basic crystalline substance that
he called 'salt of o p i u m ' ; this was thought by Serttirner [4] to be mor-
phine acid meconate and by Pelletier [9] and Robiquet [13-14] to be
narcotine.
OCCURRENCE
Morphine occurs principally in opium, which is the dried juice of
unripe seed capsules of Papaver somniferum, the average content of a
good grade of opium being about 10 per cent. [15], though it varies
between wide limits [16]. A morphine content of 21-8 per cent, in the
Hap of Papaver somniferum two hours after cutting has been reported,
hut this falls to 12 per cent, in one day as a result of atmospheric oxida-
Uon [17]. The poppy seeds themselves have been reported to be alka-
loid-free [18-23], but patents have been granted covering the extraction
of morphine and codeine from poppy seeds [24-25] and earlier workers
also claimed to have isolated morphine from this source [26-28].
Morphine is stated to appear in the plant thirty-six days after sprouting
of the seed [18].
I n addition to Papaver somniferum morphine occurs in the blue
poppy [Fructus papaveris] [29] and has been stated to occur in Papaver
orientate [30], but this has never been substantiated [31-33]; in Arge-
'rnone mexicana [Papaver spinosum] [34] (unconfirmed [35-37]); inPapaver
r/ioeas [38-39] (other workers have found only rhoeadine in this plant
I-10-44]), and in Escholtzia califomica [45] (unsubstantiated [46-48]).
Ladenberg [49] said that morphine occurs in American hops and
Willianison [50] isolated from these a base 'hopeine' that he said
oloHoly resombled but was not identical with morphine, together with
' inomorphmo', the identity of which with morphine was not eliminated.
Chapman [51] found no trace of morphines in cultivated hops.
16 M O R P H I N E AND ITS ISOMEBS CH. I I
EXTRACTION
Methods of extracting morphine are given b y references [1-7, 11-12,
24-25, and 52-72 inc.]. For many years the alkaloid was isolated by the
'Gregory process' [59] in which the concentrated opium extract is
treated with a concentrated solution of calcium chloride, when calcium
meconate, lactate, and sulphate are precipitated and removed by
nitration. Concentration of the filtrate yields the 'Gregory salt'a
mixture of codeine and morphine hydrochlorides which is purified,
dissolved in water, and the morphine precipitated by ammonia. More
modern methods are now available, and these are summarized by
Kanewskaja [70] and by Barbier [71]. Morphine can be separated from
codeine chromatographically [73-75]. The extraction of morphine and
codeine in toxicological analysis is given by Wilson and Rising [76].
PHYSICAL PROPERTIES
Morphine is obtained as monohydrate as small rhombic prisms [77]
often resembling needles [78] on crystallization from aqueous methanol
and as anhydrous prisms from anisole [79-80]. Methyl [81-82] and
amyl alcohol [83] have been recommended as solvents for recrystalliza-
tion. The base is sparingly soluble in most organic solvents but readily
soluble in benzyl alcohol [84]; solubility measurements are given in
references [84-99 inc.] and a table of solubilities by Small and Lutz
[100]. The state of aggregation markedly affects the solubility [92].
Morphine, being a phenol, is soluble in alkali hydroxide solutions [101]
b u t only sparingly soluble in alkaline earth hydroxides [102-4]. I t can
be purified b y sublimation [105-12] and as a result of sublimation the
alkaloid is present in the smoke from burning opium [113].
The monohydrate [114] loses water at 100 0. [115-16] and the an-
hydrous base has m.p. 247-248 C. (253-254 C. corrected) [117]. For
crystal measurements see [81, 118-22], specific gravity [123], and re-
fractive index [81, 124-7].
The specific rotation of morphine has been given as 130-9 (23 C.
in methanol) [82], 131-7 (methanol) [81], and 70-2 for an aqueous
solution of the sodium salt at 22-5 C. [128]. Tykociner [129] has deter-
mined the rotations of a number of salts all of which give values
around 128.
TITRATION
Morphine is a strong base, the salts of which are neutral to litmus and
methyl orange. The base turns red litmus blue but does not affect
phonolphthalein in aqueous solution, though a rose colour is obtained
whon water is added to an alcoholio solution of phonolphthalein and
morphine [1!M)J. Tho base can bo Litratod with acids poUmtiomotrioally
OH. II MORPHINE 17
COLOUR T E S T S
The following colour tests have been recorded for morphine:
Colour References
base+basic magnesium hypochlorite in yellow-brown ring; 3 hrs.
HOAc layered on to cone. H 2 SO 1 purple; 24 hrs. yellow over red
'1st yellow, then orange 187
NaNO 3 + a c i d then alkali
1st red, then brown 188
w a r m + d i l . H 8 S O 4 + F e S O 4 ; add t o cone. blue 189
NH4OH
shake+PbOu in dil. H 2 SO 1 pink; add N H 3 brown 190
warm or add acid
ferric chloride blue; > colourless 54
ferric chloride+ K 3 Fe(CN) 6 Berlin blue (sensitive 1:10 s ) 191-3
diazobenzenesulphonic acid + alkali intense red 194
dilute uranyl nitrate red 195-6
b o i l + B r / H 2 0 ; neutralize+CaCO 3 ; boil bright red 197
chlorine water greon-yellow > brownish 198-9
excess H-CHO, 1 drop SnCl 2 , evaporate blue-violet 200
H 2 0 2 + N H 4 O H , stir+copper wire wine colour; gas evolved 201-2
boil+CuSO 1 soln. green 182, 203-5
CuSO 1 +trace KCN yellow-green 206
HIO3 iodine liberated 207-11
HIO3+(NHJ2CO3 yellow-gold 210-11
H I O 3 + ( N H ) 2 C O 3 + l / 1 0 0 0 FeCl 3 intense red-violet 210-11
H I O 3 + (NHj) 2 CO 3 +1/1000 FeCl 3 + oxal- blue 210-11
acetic acidj
HI03+(NH4)2C03+1/1000 FeCl3+H0Ac emerald green over red-violet 210-11
HIO 3 +(NH 4 ) 2 CO 3 + l/1000 FeCl 3 + yellowish * black 210-11
HO Ac + oxalacetic acid
silver nitrate soln. (warm) silver precipitated 212
salts + ammonium iodoxybenzoate straw to garnet 213
K 2 ClO 1 or K 2 Cr 2 O 7 brown ppt., base+chromate ' 214
iodine chloride iodine pptd. in cold 215
C u S 0 4 + s o d i u m vanadate in dil. HOAc ppt. in solns. > 0-1% 216
ESTIMATION
Numerous methods have been used for the estimation of morphine,
and of these may be cited:
(a) The isolation of the base itself [247-8].
(b) Quantitative precipitation as an insoluble derivative [249-51].
(c) The reduction of potassium ferricyanide or iodic acid [252].
(d) Colorimotric methods [251-68 inc.].
(e) Othor methods [269-301 inc.].
(/) MothodH of OHlimation of lho alkaloid in opium [302-31 inc.].
KoviowH of lho mothodH of ontimation aro available [310-11, 313, 320-
2I 1 33a 3, 2021.
CH. I I MORPHINE 19
EMPIRICAL FORMULA
A number of salts of morphine were prepared and analysed by
Choulant [334-5] and the compositions C 34 H 36 O 6 N 2 [336-7] and
G35H40O6N2 [338-41] were first suggested for the base, and it was not
until 1847 t h a t Laurent [342] gave the composition C34H38O6]Sr2 corre-
nponding to the now-accepted C17H19O3N". From cryoscopic results
ltaoult [343] advocated a C34 formula, but later investigations have
confirmed the formula C 17 H 19 O 3 N [344-6].
Morphine [1, R = H] is a tertiary base, readily forming quaternary
Halts [347-53], and contains one NMe group [354]. I t is also a phenol,
boing soluble in alkalis [101], readily coupling in alkaline solution with
diazocompounds to give azo-dyes [187, 194, 355-7], giving a blue colour
with ferric chloride [54] and forming ethers.
E T H E R S OS M O R P H I N E
Morphine methyl ether is codeine (see Chap. IV) and is readily ob-
tained by methylation of morphine under a variety of conditions
1358-84 inc.]. Other ethers of morphine are known of the type [1]
whore R = alkyl [358-60, 364, 367-9, 371, 378, 381, 385-93], hydroxy-
allcyl [360, 394], chloro- and bromoalkyl [395], methoxymethyl [396-9],
benzyl [379, 387, 400-1], aryl [402], quinolyl [403], allyl [360, 395, 404],
OH2 COOH [405], and COOR' (really an ester of carbonic acid)
1387, 406-9], and also the bimolecular ethylene-dimorphine formed by
Mm interaction of ethylene dibromide and the sodium salt of morphine
I ,'HiO, 386-7]. The alkylation of morphine in alkalis proceeds best in the
presence of reducing agents, such as alkyl oxalates, which minimize
IOHHOS due to oxidation [410]. The benzyl [411] and methoxymethyl
1111)9] ethers are converted back to morphine by hot acids. Colour tests
for benzylmorphine are given by Schneegans [400-1]. Metal derivatives
of morphine can be obtained with sodium, potassium, and calcium
I'll 2-16].
ESTERS
Morphine also functions as an alcohol, forming a urethane [11] [417]
Mild other esters. The diacetyl ester [in, R = R' = Ac] (heroin) is
obtained by the action of acetic anhydride [349, 418-19], acetylchloride
|,'IH7, 420], and ketene [421] on morphine. 3-Acetylmorphine [in,
IV H ; R = Ac] results from the partial hydrolysis of heroin [420,
422 'I I and from the esterification of morphine with acetic acid [418].
Uko heroin it can be hydrolysed to morphine by acids [418] and
JiiizyiBQH [426]. 6-Acetylmorphine [in, R' = A c ; R = H] is not pro-
(IIKHHI during the hydrolysis of heroin [422-4] but is obtainable by the
I'HHlii'lotod action of acetic anhydride on morphine [418]. Other esters
llliiliiding [rv] [427] and mixod esters are known [387, 420, 427-36 inc.].
20 M O R P H I N E AND I T S ISOMERS OH. I I
HETEBOETHERS
The alcoholic hydroxyl of morphine may also be alkylated. Methyla-
tion of the base in cold alkali gives quaternary salts of dimethylmorphine
[in, R = R ' = Me] [443-4]. Dimethylmorphine can be obtained by
dry-distillation of its methochloride [399], methylation of morphine-
N-oxide followed by reduction with sulphurous acid [399], and by
methylation of codeine benzyl-chloride and sodium amalgam reduction
of the product [445]. Morphine-6-methyl ether (heterocodeine) [in,
R = H ; R ' = Me] methiodide results from methylating morphine-3-
methoxymethyl ether [in, R = CH 2 O CH 3 ; R' = H] and heating
the product with acid [399]. The methochloride on dry-distillation
does not yield heterocodeine, which can be obtained, however, by
methylating and reducing the N-oxide of [in, R = CH 2 -OCH 3 ; R ' = H]
[399]. Heterocodeine gives dimethylmorphine with diazomethane
[399]. Other heteroethers of morphine may be prepared in the same
way [446-8].
3-Glycosides of morphine have been prepared [449-51].
THE HALOGENOMOKPHIDES
Replacement of the alcoholic hydroxyl group by chlorine occurs when
morphine is treated with phosphorus trichloride [82] or thionyl chloride
[187, 452], the product being a-chloromorphide [v], which yields a-
chlorocodide on methylation [453-4]. An a:y-shiffc of the halogen
occurs when a-chloromorphide is heated with concentrated hydro-
chloric acid [455] and when morphine is treated in the same way [455],
/3-chloromorphide [vi] being formed. This and a trichloromorphide are
by-products in the interaction of morphine and thionyl chloride [456].
Tho prolonged notion of hydroohlorio aoid on morphine yields diohloro-
dihyclrodesoxymoi'phme [vn], and this readily IGBGB hydrogen chloride
OH. I I MOBPHINE 21
to give ^-chloromorphide [456-7]; it and /?-chloromorphide are inter-
mediates in the conversion of morphine to apomorphine [456, 458] (see
Chaps. V I I I and X X I I ) . Catalytic reduction of [vn] affords desoxy-
morphine-C [vin] and dihydrodesoxymorphine-D [ix] [459-62] (see
Chaps. V I I I and IX).
APOMORPHINE
lfl xtensive rearrangement and dehydration occurs when morphine is
llHiiUid with concentrated hydrochloric acid at 140-150 C. and apo-
inoi'pMne [x] is produced [467-8]. The same substance is formed when
Mio alkaloid is heated with phosphoric acid [469-71] and zinc chloride
I 17 2 'IJ. This reaction and the properties of apomorphine are fully
(HiiiHidorod in Chapter X X I I . Prom the interaction of morphine and
(H)(I(MiIO and hydrochloric acid or zinc chloride Wright reported the
jirodiiotion of a desoxymorphine [475-6] and ill-defined amorphous
NillmUncos claimed to be polymers of morphine, codeine, and apomor-
phlno [475-88 inc.]; these substances are doubtless complex mixtures.
Tlio 'femlphomorphide' obtained by the action of sulphuric acid on
morphine at 150-160 C. [489-90] (belioved by Matthiessen and Wright
[4(17 HJ to bo apomorphine) like the substanoo obtained by the action of
22 M O R P H I N E AND I T S ISOMERS CH. I I
REDUCTION
Catalytic hydrogenation [494-9] and electrolytic reduction [500] of
morphine affords dihydromorphine [xi], which can also be obtained by
the demethylation of dihydrocodeine; the optical antipode can be pre-
pared in the sinomenine series from (+)-dihydrocodeine [502-3] (see
Chap. X X V I ] . Dihydromorphine can be esterified [504], converted into
ethers [371, 504], heteroethers [446-8], and di-ethers [505]. Dihydro-
morphine dimethyl ether is identical with tetrahydrothebaine [505-7];
it can be demethylated to dihydromorphine [506-7].
OXIDATION
Morphine is very readily oxidized, reducing gold [18] and silver
[18, 212] salts to the metal; the platinichloride decomposes in hot water,
presumably with oxidation of the alkaloid [508]. Mild oxidation of
morphine with a variety of reagents such as alkaline potassium forri-
cyanide [509-13], nitrous acid [514-17], and atmospheric oxygen in
ammonia [518] causes linking of two molecules (in the 1:1' or 2 : 2 '
positions?) to give pseudomorphine (see Chap. III). More vigorous
oxidation, with alkaline permanganate, gives only syrupy products
[519]. Opponauer oxidation of dihydromorphine affords dihydromor-
phinone [xn] in 71 per cent, yield [520]. An amine oxide is formed by
hydrogen peroxide oxidation of the base (see below).
CATALYTIC REARRANGEMENT
Dihydromorphinone [xn] is also obtainable directly from morphine
by rearrangement on heating solutions of the alkaloid in alcohol with
[521-5] or without [526] acid, with [521-3] or without [524-6] hydrogen,
in the presence of noble metal catalysts.
H O M A M DBGEABATION
Alkaline degradation of morphine methiodide cannot be achieved
owing to formation of a phenol betaine [xv] [349, 530]. However,
degradation can be effected by heating the methiodide with acetic
anhydride and sodium acetate when the whole of the basic side-chain is
lost and diacetylmorphol [xvi] is formed [531] (see Chap. X X V I I ) .
M O R P H I N E -N- O X I D E
N O K M O R P H I N E AND ITS D E R I V A T I V E S
Heroin [in, R = E'== Ac] reacts with cyanogen bromide with
replacement of the NMe group by N CN and production of diacetyl-
cyanonormorphine [xxiv, R Ac] [550-2]. Hydrolysis of the latter
affords first cyanonormorphine [xxiv, R = H] and finally normorphine
[xxv] [552]. Cyanonormorphine can be converted into ethers [552-4]
and these can be hydrolysed to ethers of normorphine [553-4], -
chlorocyanonormorphide [xxvi] can be prepared by the action of
cyanogen bromide on a-chloromorphide [555] and is converted to
8-diethylaminocyanonormorphide [xxvn] on heating with diethyl-
amine [555] (See Chap. VIII).
N-alkylnormorphines can be prepared [554, 556] and these lose the
N-alkyl group when treated with cyanogen bromide if the group is
Hinallor than C 5 ; with C5 and larger groups ring-fission occurs [554].
26 M O R P H I N E AND ITS ISOMERS
Dihydroheroin can be converted to diacetylcyanodihydronormor-
phine [550, 552, 555], and this can be hydrolysedto dihydronormorphine
which is also furnished by catalytic reduction of normorphine [555].
RQ HQ
RO
NEt,
[XXIV] [XXV] [XXVI] [XXVII]
OZONOLYSIS
The ozonolysis of dihydrocodeine and dihydroethylmorphine with
opening of the aromatic ring to give ozodihydrocodeine [ x x v m ,
R = Me] and ozodihydroethylmorphine [xxvin, R = E t ] [558] is
discussed in Chapter IV. These products on hydrolysis afford the same
dihydromorphinic acid [xxix] [558] and on further ozonolysis the same
dihydrocodinal [xxx], which results directly from the ozonolysis of
dihydromorphine [559].
MISCELLANEOUS REACTIONS
(a) Phenanthrene is obtained by the zinc-dust distillation of mor-
phine [560-2] together with ammonia, trimethylamine, pyrroline,
pyridine, quinoline [561], and 'morphidine', a mixture of two bases,
G 17 H 15 N and C 17 H 13 N, probably derived from phenanthrene [562-3].
(/>) Fusion of tho alkaloid with potassium hydroxide affords methyl-
arnino [5JO, 504] and. protooatoohuio acid [519], while heating with
ftlooholio potowh a t Jiigh temperatures provides othylmothylamino [565].
OH. I I MORPHINE 27
CH8-OH CH5OH
[XXI] [XXXII] [XXXIII] [XXXIV]
28 M O B P H I N E AND ITS ISOMERS OH. II
(iii) Dihydromorpbinone [xn] on heating with methanolic aqueous
formaldehyde and calcium oxide yields 7-bis(hydroxymethyl)-dihydro-
morphine [xxxiv] [606].
(iv) Demethylation of neopine [xxxv] affords neomorphine [xxxvi]
[607] (see Chap. VII).
STEREOOHEMisTKY
Following a study of a large number of compounds Emde [608] con-
cluded t h a t the contributions of the various asymmetric centres in
morphine to the total rotation are in the senses shown in [ x x x v n ] .
a-ISOMORPHINE
This base is obtained by the hydrolysis of a-chloromorphide [454,
463-4] and of bromomorphide [82, 454, 609]. I t differs from morphine
only in the spatial arrangement of the alcoholic group as it can be
methylated to isocodeine [454, 609-10] which is known to give the same
codeinone on oxidation as does codeine [6U]. Other ethers and hetero-
ethers can be prepared [446]. With phosphorus trichloride a-iso-
morphine yields what is probably /3-chloromorphide [82, 609] and
bromomorphide with phosphorus tribromide [609]. Catalytic reduction
of the base affords a quantitative yield of dihydro-a-isomorphine,
which can be methylated to dihydroisocodeine [63 2]. Mild oxidation of
a-isomorphine affords a-pseudomorphine [613]. Alkaline degradation of
a-isomorphine methiodide gives only a phenol betaine, but acetic
anhydride degradation gives diacetylmorphol [xvi] [82].
j3-ISOMORPHINE
This isomer of morphine also results from the hydrolysis of a-
cbloromorphidc [453-4, 464] and of bromomorphide [454]. I t differs
from morphine in having the double bond at C-6:7 and the alcoholic
group at C-8, as is shown by its methylation to allo-i/t-codeine [453-4,
611] which can be degraded to 3:4:8-trimethoxyphenanthrene [538]
(soo Chap. IV). jS-Isomorphine [ x x x v m ] on oatalytio reduction under-
goes opening of tho oyolio otbor link to give totrahydro-jS-isomorpbine
OH. Ii ,S-ISOMORPHINE 29
y-ISOMOBPHINE
This base, which has also been called neoisomorphine, can be pre-
pared like a- and /3-isomorphines by the hydrolysis of a-chlorocodide
[453-4, 463, 611] and of bromomorphide [454]. It differs from /J-
isomorphine only in the arrangement of the alcoholic group, as is shown
by its methylation to i/i-codeine [453-4, 463, 611], which on oxidation
gives the same ;/<-codemone as does allo-^r-codeine [464, 611, 615].
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Refs.
Morphine phenylacetate . 92 650, 87,
88
diallylbarbiturate 258 H2O needles 573, 575
phenylethylbarbiturate 250 needles 574
violurate . . . . . -43-7 30 665
111
diphenylthioviolurate 93 666
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent
6-benzoylmorphine. 269-270
6-benzoylmorphmc hydrochloride 241-243
bitartrate . . . . c.136-138
Dibenzoylmorphine 189-190-5 EtOH prisms
hydrochloride H a O cryst.
platinichloride . amorph.
ethiodide-iH,0 85% cryst.
EtOH
y-hydroxybenzoylmorphine D. 230 50% leaflets
EtOH
hydrochloride . cryst.
methobromide . cryst.
2>-acetoxybcnzoylmorphine D. 232 EtOAc needles
hydrochloride . prisms
methobromide . prisms
2>-carbomethoxybenzoyImorphine D.175-176 EtOH prisms
hydrochloride-EtOH . D. 190 EtOH
3-benzenesulphonylmorphine . 165 EtjO
benzenesulphonate 140 HjO needles
#-toluenesulphonylmorphine . 61-68
hydrochloride . 118 plates
picrate . . . . 190-194 EtOH
Morphine-sulphuric acid '2HjO HjO needles
Carbomothoxymorphine . 120 cryst.
hydrochloride . cryst.
sulphate . . . . 225
platinichloride . cryst.
Acetylcarbomethoxymorphine. 168 prisms or
needles
Carboetlioxymorphine /123-124 -143-7 Eton
\ 113
hydrochloride
sulphate .
platinichloride .
oxalate 2II a 0 HjO +
EtOH
bitartrate . 121-X22d. EtOH HjO
Acetylcarboethoxymorphine 155 EtOH needles
hydrochloride . D. 185 needles
platinichloride . 210 needles
Oarbopropoxymorphine
hydrochloride .
platinichloride 2HjO
Acetylcarbopropoxymorphine 120 needles
Carboisopropoxymorphine
Carboamoxymorphine
Morphine phonylurcthane 127-130
Morphino-3-methyl ether: see codeine
Morphine-6-methyl ether (hctcro-
codeine) 242 EtOH
hydrochloride 2H a 0 103 HjO -153-7 25 HjO
methochloride . > 270 H,0 +
EtOH
Morphine-3-ethyl ether (ethyl- 93 H2O prisms
morphine; codethylin)
- hydrochloride -H 2 O 12S-125d,
- sulphate 5H a 0 . 207 HJO +
EtOH
- camphorsulphonate H2O 154 -55-5 HjO
- o-guaiacolsulphonate . HjO cubes
- styphnate . 115
- othylallylbarbiturate . 67
- ethylphenylbarbiturate 87
- diallylbarbiturate 285
- methobromide HjO . 267-268 prisms
mothiortldo
ntlinbroinUlu 225 11,0 + needles
MH)II
olhloilldo . HlIOII 111-ClIIi 1 H
5447.1 J)
U M O R P H I N E AND ITS ISOMERS
Solvent
for Crystal Specific
0
Compound m.p. C recrystn. form rotation Temp. Solvent Refs.
Morphine-3-ethyl ether N-oxide 220-221 H2O needles 542
N-oxide hydrochloride 542
N-oxide sulphate 542
N-oxide nitrate . . . . 542
M.orphine-6-ethyl ether -H2O . 110-112 BtOAc -178-8 23 EtOH 446
hydrochloride 3H2O . 241-243 H1O -134-9 24 H2O 446
hydrobromide'2HjO . 285-287 H2O -119-2 23 H2O 446
hydriodide-2H 2 O 171-174 H2O -115-8 24 H2O 446
and 282
perchlorate . . . . 249-250 H2O -126 24 EtOH 446
methiodide . . . . 255-265 -104-6 24 H2O 446
Morphine-3--chloroethyl ether 75-76 n2o 395
and 105
(anhydrous) . . . . 118-120 395
hydrochloride-H 2 O 150-151 Acetone 395
+ H2O
hydrochloride (anhyd.) 166-168 395
hydriodide . . . . 212-213 H2O + 395
MeOH +
HI
sulphate 115-120 BtOH needles 395
and 235-
240
phosphate . . . . D. 110 395
oxalate . . . . . 85-87 395
Morphine-3-|3-bromoethyl ether 135-136 395
and 185-
187
impure hydrochloride 210-230 395
Morphine-3-m-propyl ether iH0 69-70 389,393
hydrochloride-HjO 111-114 393
hydrochloride (anhyd.) 146-153 393
Morphine-3-O: /3'-dichloro-isopropyl)-
ether . . . . . 115 395
hydrochloride . . . . 147 395
Morphine-3-n-butyl ether not cryst. 393
hydrochloride'H 1 O 101-104 393
hydrochloride (anhyd.) 119-122 393
Morphine-3-benzyl ether (benzyl-
morphine) . . . . . 693-4
hydrochloride JH 2 O . H2O 695-6
N-oxide . . . . . 236-238 EtOH -53-2 23 EtOH 446
ethanesulphonate 697-700
propanesulphonate 697-700
6-benzoylmorphine-3-benzyl ether . 130-135 688
Morphine-3-allyl ether . 67-68 395, 404,
573
hydrochloride'H 2 O 130-132 -85-7 19 H2O 395
hydrochloride (anhyd.) 152-153 395
hydriodide . . . . 225-226 H 2 O+ H l prisms 395
acid sulphate . . . . 202-203 BtOH 395
sulphate-H 3 O . . . . 167-168 H2O 395
sulphate (anhydrous) . 172-173 BtOH 395
dihydrogen phosphate 186 Acetone 395
+H2O
phosphate . . . . 100 395
oxalate . . . . . 103 and BtOH 395
203
Morphine-3-methoxymethyl ether . 94-96 needles 399, 398,
396
sulphate-10H 8 O cryst. 399, 398,
396
methiodide . . . . 225d. BtOH needles 399, 398,
396
N-oxide 448
Moiphlno-8-0-hydroxyotliyl other 190 -124-8 MeOH 394
Movphlno-8-(>art)OxymoU>yl othor B. o. 192 BtOH neodlos 405
palUMliim milt noodlos 405
Morphlmi-OiU-illnlti'ophmiyl) ollior . ., 402
Mi)r|ihtiii'-ll-i|iilnnlyl ol.lml' 158 iiioir prlMin 403
' liyilrmililurliln , liiiorly 403
"
nryjili.
OH. I I M O R P H I N E AND I T S ISOMERS 35
Solvent
/or Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Ms.
Morphine-3-quinolyl ether sulphate
-3H2O . . . . 257d. H2O -66-5 dil.HCl 403
chromate . . . . 403
picrate . . . . 250-252d. cryst. 403
tartrate . . . . 98d. EtOH prisms 403
Morphine-3-benzyl-6-methyl ether 446
hydrochloride . 233-236 H2O -88-9 28 H2O 446
acid sulphate 247-2*9 H2O -90-1 25 H8O 446
methiodide 155-157 50% -75-8 24 50% 446
BtOH BtOH
Morphine dimethyl ether: see codeine methyl ether (Ohap. IV).
Morphine-3-methoxymethyI-6-methyl
ether
methoehloride D. 200
methiodide 253d. 80%
EtOH
Dimorphine-3:3'-ethylene ether 188 EtOH + needles
H2O
hydrochloride . cryst.
Dimorphine-3; 3'-pentamethylene
ether . . . . 70-100 amorph.
Morphine glucoside c.183-193 50% needles
EtOH
Morphine tetraacetylglucoside 154-156 EtOH + needles
H2O
hydrochloride . c. 22Od.
o-Morphine 3-|3-6-cellobioside-/3-<Z-
glycoside . . . . 120-121 amorph.
/9-Morphine3-/3-6-ceIlobioside-/3-tf-
176-177 cryst.
Morphine amino acid estors and
derivatives amorph.
])ihydromorphine-H 2 0 . 155-157 EtOH
hydrochloride . prisms
hydriodide 275
picrate . . . . 139 prisms
diallybarbiturate 125 H2O
Rncemate with antipode from sinO'
menine series 154
hydriodide 261
- methiodide 267
( I )dihydromorphine 159 + 151-5 29 EtOH
- hydriodide + 87-9 29 H2O
methiodide + 74-9 30 H2O
I acotyldihydromorphine 165-167 needles
hydrochloride . cryst.
l)lhydromorphine-3-methyl ether: see dihydrocodeine (Chap IV).
Dlliydromorphine-6-methyl ether
(1 Mhydroheterocodeine) 217-219 BtOH -178-0 26 BtOH
hydrochloride . 299-299-5 -136-5 26 H2O
hydriodide 269 H2O -98-9 25 H2O
- porchlorate 258-260 H2O -110-0 28 H2O
- nold fumarate . 215-216 95% -110-0 28 H2O
EtOH
methiodide 260-261 MeOH -91-4 28 MeOH
IHIiyilromorphine-3-ethy] ether oil -135-9 24 EtOH
iKild citrate'H 2 O 158-159 EtOH
IKiId Ijirtrato 167 -59-4 25 H2O
iniil.lilodide 260 BtOH -66-9 25 H2O
111 I iyil rcmiorphine-6-ethyl ether 189-190 EtOAc -164-8 23 BtOH
li,VilmiiIilorIdo-3H20 95-110 H2O -121-7 24 H2O
and
274-276
hyilrol>romldo-2H,0 . 282-284 H2O -125-1 25 H2O
Iiyili'lodldo 291-293 H2O -110-6 25 H2O
imriililornlo 234-235 H2O -98-0 23 BtOH
mnUiloilldo 250-251 -79-4 25 MeOH
DlliyilnitiiDi'iihlno-R-bonnyl other 95-97 ElOAc -88-1 24 EtOH
hyil rocililorUln 11 0 . 21)3-235 H1O -52-1 20 H2O
li.vilriiliriiiiildO'll.O . 198-11)5 11,0 -44-0 24 JT1O
I- hyilrloilldu 210-217 11,0 .. -8 liil Jl,0
36 M O R P H I N E AND I T S ISOMERS CH. I l
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Solvent
Dilrydromorphine-3-benzyl ether per- 188-192 20% -59-5 23 BtOH
chlorate EtOH
methiodide . . . . 242-244 MeOH plates -43-2 24 MeOH
N-oxide . . . . .
DIhydromorphine-3-methoxymethyl
ether . . . . . 99-101 acetone -164-5 24 EtOH
hydrochloride . . . . 124-126 -71-8 24 HaO
sulphate . . . . . 49 -72-8 24 H2O
methiodide . . . . 201-203 BtOH -61-8 24 H2O
N-oxide . . . . .
IMhydromorphine dimethyl ether: see dihydrocodeine methyl ether (Ohap. IV)
Dihydromorphine-3-benzyl-6-methyl
ether . . . . not cryst.
methiodide 155-157 EtOH -54-6 24 H2O
l-bromomorphine-H 2 0 . BtOH prisms
hydrochloride 3HiO . H2O needles
hydrobromide ' 3 H 1 O . D. 221 H2O needles
methiodide H2O 252 H2O prisms
methohydroxide
Dlacetylbromomorphine 208 MeOH
hydrobromide . needles
methiodide ' I i H j O 200
Tetrabromomorphine (two isomers)
a-hydrobromide 218
J3-hydrobromide 178
a-sulphate-H 2 0
a-oxalate . . . .
barium salt
Tribromomorphine
l-nitrodiacetylmorphine .
2-nitromorphine 225d. EtOH orange
needles
hydrochloride . 2483. dil. HCl yellow
needles
ammonium s a l t . D.173-174 dark red
leaflets
sodium salt D. > 220 garnet
needles
silver salt . . . . 181-182d. black
2-aminomorphine . 258 BtOH plates
dihydrochloride . BtOH 90
picrate . . . . B. 172 H,0 needles
2-aminodihydromorphine
hydrochloride . . . D. 325
Tribenzoyl-2-aminodihydromorphine 185'
Nitrosomorphine ? . D.
Diazomorphine anhydride
hydrochloride . D. c. 98
2-hydroxymorphine hydrochloride amorph.
1-nitroethylmorphine 166-167
1-aminoethylmorphme . 115-116
Acetyl-1-aminoethylmorphine .
hydrochloride .
Diacetyl-1-ammoethylmorphme 156
2-phenylazomorphine 175d. needles
2-(2'-methylphenyl)azomorphine 21Od. amorph.
2-(4'-ehlorophenyl)azomorphine > 300 amorph.
2-(2': 4': 6'-tribromophenyl)azo-
morphine . . . . > 300 amorph.
2-(4'-hydroxyphenyl)azomorphine > 300 amorph.
2-(2'-methoxyphenyl)azomorphine > 300 amorph.
2-(2'-nitrophenyl)azomorphine > 300 amorph.
2-(3'-nitrophenyl)azomorphine > 300 amorph.
2-(4'-nitrophonyl)azomorphlne. > 300 amorph.
2-(a-iiaphthyl)azomorphino > 300 amorph.
2-bonzklinototrazomorphlno . > 800 amorph.
1-aootomorphlno . 200-282-5 40% -156 20 BtOH
HtOH
hydroohlorldi) . 280-287 1)5% -121 20 H2O
TOU)It
porolilorivtitt . 2(H ana-n H1O -III 20 HK)II
l)lA0lyl*J-Maalmw)ri>li1nu , 2(10-2IW JSU)II -207 20 (JIK)I1
OH. I I M O R P H I N E AND ITS ISOMERS 37
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Reft.
Diacetyl-1-acetomorphine hydro-
chloride . . . . . 537
6-acetyl-l-acetodihydromorphine 242 MeOH -97-2 20 OHOl8 538
3:6-diacetyI-l-acetodihydromorphine glass 538
Morphine-N-oxide . . . . 247-275 50% prisms 542-3
EtOH
nitrate . . . . . 206-208 543
Acetylmorphine-N-oxide 3H a 0 205 -144 EtOH 547
Dihydromorphine-N-oxide D. 261 EtOH plates 540
Oxidodimorphine sulphonic acid 280 needles 545-6
Morphine sulphonic acid'H 2 O . > 300 prisms 543-6
Dihydromorphine-N-oxide sulphonio
acid . . . . . . D. > 360 prisms 546
a-dihydromorphine sulphonic acid . D. > 360 50% scales 546
EtOH
/9-dihydromorphine sulphonic acid . D. > 360 546
Diacetylmorphine sulphonic acid
(heroin sulphonic acid) > 280 539
Normorphine-I 2 -H 2 O 272-273 needles 552, 550
hydrochloride'HjO D. 305 552
sulphate 3H2O . . . . cryst. 552
platinichloride 3H2O . D.230-231 552
picrate . . . . . 552
Dibenzoylnormorphine . 208 552
Triacetylnormorphine 164 EtOH 552
Normorphine-3-mothyl ether: see norct deine (Cha p. IV).
Normorphine-3-ethyl ether 156 554
hydrochloride -2H3O . 295 H2O needles 554
platinichloride . . . . 299 554
Normorphine-3-isoamyl ether . 100 552
hydrochloride . . . . 278 Et 2 O + 552
EtOH
Normorphine-3-allyl ether 164 EtOH 554
hydrochloride'H 2 O 240 H2O needles 554
platinichloride-H 3 O . D. 250 554
Normorphine-3-p-nitrohenzyl ether . 180 EtOH 553
hydrochloride . . . . D. 297 553
Dinormorphme-3:3'-pentamethylene
ether . . . . . . 133-132 554
dihydrochloride . . . . 235-240 554
platinichloride . . . . D.240-250 554
N-allylnormorphine 92-93 556
hydrobromide . . . . 126 556
N-nitrosonormorphine D. 267 EtOH needles 557
3-ethyl ether . . . . 205 554
3-isoamyl ether . . . . 186 552
3-aIlyl ether . . . . 176 554
Macetyl-N-nitrosonormorphine 202-203 EtOH + 557
H1O
IM-(N-nitrosonormorphine)-3:3'-
pcntamethylene ether . 145-150 554
l)i-(N-ammonormorphine)-3:3'-
pentamethylene ether . 140-145 554
N-(phenylthiocarbamino)-normor-
phine . . . . . 245 554
W -earbaminonormorphme-S-p-
nminobenzyl ether 297 553
('yanonormorphine. 295-296 EtOH 550, 552
1 Hucctylcyanonormorphine 240 EtOH 552
KonKoylcyanonormorphine 265 EtOH 552
(!yanonormorphine. 240 552
- 3-othyl ether . . . . 225-226 554
- 3-isoamylether . . . . 225 552
- il-allyl other . . . . 221 554
- 3-j)-nltrobenzyl ether . 229 EtOH 553
DHcyiuionormorphineJ-S; 3'-penta-
inolhylono othor . . . . 220-230 554
Ulliyilronormorpluno 207 noodles 550, 555
hydrochloride . . . . 303 uoodlos 555
pliilIrLlcliloiItUi . . . . ppt. 555
(lyimfMimtlUydroiiiorplilnn Ul)I 151,'(W ItmilolK 550, 555
UlKunlylayunononUliyilruinoriiJiluu . 138-100 uoodloi 650, B62
38 M O R P H I N E AND I T S ISOMERS OH, II
Solvent
for Crystal Specific
Compound m.p. "O. recrystn. form rotation Temp. Solvent Eefs.
Morphine quinitrol 187
nitrate-H 2 O . . . . orange 187
prisms
Morphinie acid . . . . 187
hydrochloride 2H2O . HVO needles 187
nitrate-H a 0 . . . . 187
oxime hydrochloride . i>. cryst. 187
Dimorphenylmethane amorph. 566
hydrochloride . . . . 566
6-methyldiliydromorphine 209-211 acetone -147-0 20 EtOH 603
hydrochloride . . . . 308-309 Et2O+ -121-0 20 EtOH 603
EtOH
methiodide . . . . 277-278 MeOH -86-8 20 EtOH 603
7:7-bis-[hydioxymethyl]-dihydromorphine: see Chapter X .
Other substituted dihydromorphines: see Chapter XIX.
o-isomorphine 251-252 BtOAc + needles -167-0 15 MeOH
MeOH
hydrochloride . EtOH -150-0 20 H2O
hydrobromide-H 2 O . H2O -127-2 15 H2O
methiodide . . . . 276 H2O -91-5 23 H2O
methohydroxide
Biacetyl-a-isomorphine . not cryst.
methiodide . . . . 241-242 MeOH needles
a-isomorphine-3-methyI ether: see isocodeine (Chap. IV).
oi-isomorphine-6-methyl ether
(heteroisocodeine) . . . 206-207 EtOH -185-5 22 MeOH
methiodide . . . . 227-228 EtOH -105-4 22 H2O
a-isomorphine-3-ethyl ether . . 128-130 -143-7 23 EtOH
methiodide . . . . 243 EtOH -91-6 21 H2O
a-isomorphine-6-ethyl ether . . 161-162 Distilled -205-1 22 MeOH
hydrochloride . . . . 247-248 -164-2 24 H2O
hydrobromide . . . . 255-258 H2O -150-2 24 H2O
hydriodide . . . . 264 H2O -132-7 24 H2O
methiodide . . . . 229-231 EtOH -131-3 24 H2O
Dihydro-a-isomorphine . . . 224-226 -125-8 19 MeOH
hydrochloride . -112-0 23 H2O
hydrobromide . -97-9 H2O
binoxalate -91-9 22 H2O
methiodide -80-4 23 H2O
Dihydro-a-isomorphine-3-methyl ether: see dihydroisocodeine (Chap. IV),
Dihydro-a-isomorphme-6-methyl
ether 198-200 -118-1. 25 EtOH
hydrochloride . . . . 273-275 H2O -111-1 24 H2O
hydriodide . . . . 287-288 H2O -85-2 24 H2O
methiodide . . . . 245-248 EtOH -77-9 24 H2O
Dmydro--isomorphmc-3-ethyl ether 86-91 EtOAc -110-0 24 JIeOH
acid tartrate-H 2 O . . . 109-112 acetone -66-0 23 H2O
methiodide . . . . 277 80% -76-2 23 H2O
EtOH
Dihydro-a-isomorphine-6-ethyl ether 210-212 EtOH -128-0 24 EtOH
hydrochloride . 300 -125-7 24 H2O
hydriodide 287 -99-5 24 H2O
methiodide 256-258 EtOH -86-1 24 H2O
/3-isomorphine-iEtOH . 182 EtOH -216-2 17 MeOH
hydrochloride . H2O needles -200-8 11 H2O
methiodide 250 H2O -146-1 23 H2O
/3-isomorphine-3-ethyl ether oil
perchlorate 264-266 H 2 O -113-2 25 40%
EtOH
acid sulphate 195-198 H2O -136-3 24 H2O
fumarate . 172-175 -100-3 24 EtOH
P-isomorphine-6-ethyl ether 209-211 EtOH -60-1 24 EtOH
Dihydro-j3-isomorphme -H2O 202-203 -104-0 22 MeOH
hydrochloride . -98-7 23 H2O
hydrobromldo , -87-0 23 H1O
acid fiimarato . -81-8 22 H8O
IDlhydro-fl-lsomorplilno-a-othyl ottior oil
porolilumto
plomto
231-234
187-180
TI1O
60%
-M-B
-04-8
2J5
21)
ri.'o
Eton
MtOlI
'JWaliyilro-Mnoinoj'pliliin 240-247J, - 00-4 22 .10%
UOAo
CH. II MORPHINE AND ITS ISOMEBS 39
Solvent
SOT Crystal Specific
Compound m.p. C. reerystn. form rotation Temp. Solvent Refs.
y-isomorphine BtOH 278 BtOH -94-0 15 EtOH 453-4,
463-4
hydrochloride . . . . 314 -76-0 15 HjO 463
hydrobromide . . . . 298 -71-0 15 H2O 463
methiodide . . . . 293 -50-0 15 HjO 463
Diacetyl-y-isomorphine . not cryst. 463
methiodide . . . . 267 BtOH needles -24-0 15 HJO 463
y-isomorphine-3-methyl ether: see i^-codeine (Chap. IV).
y-isomorphine-6-methyI ether (hetero-
O-
</>-codeine) . 239-241 BtOH -79-5 23 MeOH
hydrochloride . 274-276 H,0 -48-6 22 H2O
hydriodide 185-188 H,0 -48-7 21 HjO
y-isomorphine-3-ethyl ether 183-184 EtOH -75-0 22 MeOH
hydrochloride . 298-300 -62-7 24 H8O
methiodide 252-253 70% -40-8 21 HjO
BtOH
y-iaomorphine-6-ethyl ether 215-220 BtOH -43-5 23 MeOH
hydrochloride-2HaO . 287-290 H8O -30-5 23 H,0
hydriodide -HjO 276-277 HjO -23-2 22 HjO
Dihydro-y-isomorphine . 127 and -35 25 95%
221 EtOH
hydrochloride . 300-302 plates -27-4 28 HjO
hydriodide 285-288 needles -21-7 25 HJO
perchlorate needles -24-0 25 H2O
salicylate . 131-5- -22-8 27 HjO
132-5
methiodide 255-257 plates -21-0 27 HJO
Bihydro-y-isomorphine-3-methyl ether see dihydro-i/'-codeine-A (Chap. IV).
Dihydro-y-isomorphine-6-methyl
ether . . . . . 235-237 EtOH -83-4 25 EtOH
hydrobromide . . . . 256-258 HjO -55-4 25 H2O
hydriodide . . . . 185-187 H2O -52-8 25 HJO
Dihydro-y-isomorphine-3-ethyl ether 158-159 EtOAc -36-2 23 MeOH
fumarate . . . . . 180-192 EtOH -23-7 23 HjO
methiodide . . . . 252-253 70% -40-8 21 HJO
EtOH
Dihydro-y-isomorphine-6-ethyl ether 220-223 EtOH -20-2 25 EtOH
hydriodide 277-281 HjO -9-1 25 H8O
methiodide 250-252 80% -7-2 25 HJO
BtOH
Tetrahydro-y-isomorphine not cryst.
/ -8-0 24 H2O
hydrochloride . 278-280 HOAc needles
1-35-0 27 HjO
hydriodide 280-290 H2O -1-8 27 HJO
BIBLIOGRAPHY TO CHAPTER II
1. SERTtrRNER, Trommsdorff's Journal 10. SBGTJIN, Ann. CMm., 1814,92, 225.
der Pharmazie, 1805 (1), 13, 234. 11. RoBiQtTBT, Ann. Ghim. Phys., 1817
2. ibid., 1806 (1), 14, 47. (2), 5, 275.
3. ibid., 1811 (1), 20, 99. 12. Gilbert's Ann. der Physik, 1817,
i. Ann. Chim.Phys., 1817 (2), 5, 21. 57, 163.
5. Gilbert's Ann. der Physik, 1817, 13. J. Pharm., 1831 (2), 17, 637.
55, 56. 14. Ann., 1832, 2, 267.
6. ibid. 57, 192. 15. JEBMSTADT, Das Opium (Verlag Hart-
7. ibid. 1818, 59, 50. leben, Wien, 1921).
8. KEOMEKE, Priedrich Wilhelm Sertur- 16. ABIMA a n d IWAKIBI, Sept. Inst. Sd.
ner, der Entdecker des Morphiums Bes. Manchoukuo, 1938, 2 , 221.
(Fischer, Jena, 1925). 17. VOKOZHTZOV and TROSHCHENKO,
O. PTsrXnmiKR, Ann. Ghim. Phys., 1832 Cornpt. Mend. Acad. Sd. U.S.S.R.,
(2), 50, 240, 1935, 2 ,555,
40 MORPHINE ANDITS ISOMERS CH. I l
18. KERBOSCH, Arch. Pharm., 1910, 248, 56. DUBLANC, Ann., 1832, 4, 232.
536. 57. DUFLOS, J. Ghem. Phys. (Schweigger-
19. SAOC, Ann. GHm. Phys., 1853,27, 473. Seidel), 1831,61, 105.
20. CLATTTEIATT, J. Pharm., 1889 (5), 20, 58. R O B I N E T , J. Pharm., 1827 (2), 13, 24.
161. 59. GREGORY, Ann., 1833, 7, 261.
21. MAOH, Landwirtschaftl. Versuchssta- 60. PATZUKOV, Russ. Pat. 127 (1922).
tionen, 1902, 57, 419. 61. B U S S E and BITSSE, KHm. Pharm.
22. MTJLLER, Arch. Pharm., 1914,252, 280. Prom., 1933, 127.
23. HEIDUSCHKA, Schweiz. Apoth. Ztg., 62. MALLORY, U.S. Pat. 2,062,324 (1 Dec.
1919, 57, 447. 1937).
24. KLYACIIKINA, BUSS. Pat. 53,168 (31 63. H O F F M A N N - L A ROCHE and Co., D.
May 1938). R.-P. 640, 859 (1937); Frdl. 2 3 , 449.
25. ZAOINTS, M E B M S , and LABEN- 64. Brit. Pat. 457,433 (27 Nov.
SKii, Russ. Pat. 53,224 (31 May 1936).
1938). 65. French Pat. 804,543 (26
26. AOCABIE, J. CHm. mid., 1832, 431. Oct. 1936).
27. Jahresber. Ghem., 1834, 4, 250. 66. -Swiss Pat. 186,666 (1 Dec.
28. MITEEIN, J. Pharm. CHm., 1853, 2 3 , 1936).
393. 67. MOBGAN, Ind. Eng. Ohem. (Anal.
29. FTJCHS, Pharm. Monatsh , 1932, 13, Edn.), 1937, 9, 387.
223. 68. GINSBTTRG and GAVBILOV, J. Applied
30. P E T I T , J. Pharm., 1813 (1), 1, 170. Ghem. U.S.S.R., 1947, 20, 120.
31. GADAMEB, Z. angew. Ohem., 1913, 26, 69. OPAEINA, RUSS. Pat. 67,940 (1947).
625. 70. KANEWSKAJA, J. pr. Ghem., 1924 (2),
32. Per., 1914, 24, 35. 108, 247.
33. K L E E , Arch. Pharm., 1914, 252, 211. 71. BABBIER, Ann. pharm. Franc., 1947,
34. CHARBONIEE, J . Pharm. GHm., 1868 5, 121; Ohem. Abs., 1948,42, 1023.
(4), 7, 348. 72. F B E Y and W U E S T , U.S. Pat. 2,132,945
35. SoHMiDT,^re^.Ptorm.,190],239,401. (11 Oct. 1939).
36. SaHLOTTEEBECK, J.A.G.8., 1902, 24, 73. L E V I and CASTELLI, Oazz. GHm. Ital.,
238. 1938, 68, 459.
37. L E PRINCE, Bull. Sci. Pharmacol., 74. Ara. UoI. (Sao Paulo), 1939,
1909, 16, 270. 23, 263.
38. DIETERICH, Pharm. Zeit. Puss., 1888, 75. Anales farm, bioquim. (Bue-
27, 269. nos Aires), 1940, 11, 6.
39. SELMI, Ber., 1876, 9, 195. 76. W I L S O N and R I S I N G , J. Am. Pharm.
40. H E S S E , Ann. Suppl., 1865-6, 4, 50. Assoc, 1939,28, 146.
41. Ann., 1866, 140, 145. 77. SCHABTJS, Jahresber. Fortschr. Ghem.,
42. Arch. Pharm., 1890,228, 7. 1854, 503.
43. R I F F O B D , J. Pharm., 1830 (2), 16, 78. D E A N a n d B R A D Y , J.G.S., 1865, 34.
547. 79. FOUQUET, Bull. Soc. GHm., 1882, 3 7 ,
44. M E Y L I N K and STBATNIK, Biichner's 477.
Re.pt. Pharmazie, 1831, 36, 143. 80. J. Pharm. GHm., 1897 (6), 5, 49.
45. B A U D E T and A D B I A N , Pharm. Ztg., 81. W H B R B Y and JANOWSKY, J. Wash.
1889, 34, 23. Acad. Sci., 1919, 9, 505.
46. SCHMIDT, Arch. Pharm., 1901, 239, 82. SOHRYVEB and L E E S , J.O.S., 1900,
406. 1024.
47. DANCKWOET, ibid., 1890, 228, 572. 83. SCHACHTRTJPP, Arch. Pharm., 1867 (2),
48. FISCHER, ibid., 1901,239, 421. 132, 1.
49. L A D E N B E E G , Ber., 1886, 19, 783. 84. F A B E E , Bull. Soc. Pharm. Bordeaux,
50. WILLIAMSON, Ohem. Ztg., 1886,10, 20, 1924, 62, 68.
38, 147, 239, 491. 85. PETTBNKOFER, Jahresber. Fortschr.
51. CHAPMAN, J.O.S., 1914, 1895. Ghem., 1858, 363.
52. ROBIQUET, Ann. OHm. Phys., 1832 86. K U B L Y , ibid., 1866, 823.
(2), 5 1 , 225. 87. FLORIO, Gazz. Ghim. Ital., 1883, 13,
53. Ann., 1833, 5, 82. 496.
54. VioniiHTUOii, ibid, 150.^ 88. Jahresber. Fortschr. Ohem,., 1883,
(55. Ooiiiaituio, Ann. Cl lam". Ph yn., 1832(2), 1343.
49, 4fi. 89. HuiKi, Z. anal. (JJwm., 18H0, 19, 222.
CH. II MORPHINE AND ITS ISOMEES 41
90. SCHINDELMEIEB, Chem. Ztg., 1901, 2 5 , 123. SCHBODEB, Ber., 1888, 13, 1075.
129. 124. K L E Y , B e e . Trae. Chim., 1903,22,367.
91. MULLEB, Apoth. Ztg., 1903, 18, 257. 125. Z. anal. Chem., 1904, 4 3 , 164.
92. PBESOOTT, Pharm. J. Trans., 1875 126. K E E N A N , J. Am. Pharm. Assoc,
(3), 6, 404. 1916, 16, 837.
93. GUILD, ibid., 1907 (4), 78, 357. 127. W E I G H T , J.A.C.S., 1916, 38, 1655.
94. G U E B I N , J. Pliarm. GMm., 1913, 7, 128. H E S S E , Ann., 1875, 176, 189.
438. 129. TYKOOYINEB, Bee. Trav. Chim., 1822,
95. SCHAVUX, Am. J. Pharm., 1913,85,439. 1, 144.
96. GOBI, Boll. cUm. farm., 1913, 52, 891. 130. LEBOY, Compt. Bend., 1899, 128,
97. ANOTHER, Arch. Pharm., 1912, 2 5 0 , 1107.
193. 131. KoLTHomr, Biochem. Z., 1925, 162,
98. SCHOLTZ, ibid. 418. 338.
99. HEIDUSOHKA and F A U L , ibid., 1917, 132. Pharm. Weekblad, 1925,62, 106.
255, 441. 133. ibid. 190.
100. SMALL a n d L U T Z , Chemistry of the 134. W A L E S , J. Ind. Eng. Chem., 1926,18,
Opium Alkaloids (U.S. P u b . Health 390.
Suppl. 1931). 135. RASMUSSEJST and SCHOU, Pharm.
101. CHASTAING, J. Pharm., 1881 (5), 4 , Zentralhalle, 1924, 6 5 , 729.
91. 136. Z. Elektrochem., 1925, 3 1 ,
102. Bull. Soc. CUm., 1882, 3 7 , 477. 189.
103. Compt. Rend., 1882, 94, 44. 137. K L E B B B , J.A.C.S., 1895, 17, 822.
104. Pip. Pharm. J. Chim. mid,, 138. E V E B S , Pharm. J., 1921, 106, 470.
1881,9, 219. 139. K L E B E B , D O H M E , and CASPABI, Z.
105. B L Y T H , J.O.S., 1878, 313. anal. Chem., 1899, 38, 200.
106. G U Y , Pharm. J. Trans., 1866 (2), 8, 140. K I P P E N B E B G E B , ibid., 1900, 39, 201.
718. 141. SCHOB, ibid., 1901, 40, 432.
107. TOTMAMT, Apoth. Ztg., 1916, 31, 148. 142. KoLTHomr, Z. anorg. Chem., 1920,
108. K B A F F T and W E I L A N D T , Ber., 1896, 112, 196.
29, 2240. 143. MOGILL, J.A.C.S., 1922, 44, 2156.
109. HBIDUSOHKA and MEISNEE, Arch. 144. MASUCOI and MOEFATT, J. Am.
Pharm., 1923, 261, 102. Pharm. Assoc, 1923, 12, 609.
110. WAGENAAB, Pharm,. Weekblad, 1929, 145. TBEADWELL and JANETT, HeIv. Chim.
66, 1121. Acta, 1923, 6, 734.
111. BOTOLFSEN and PAULSSEN, Bull. Soc. 146. MULLBB, Z. Elektrochem., 1924, 30,
Chim., 1946, 390. 587.
112. J A N O T and CHAIGENEAU, Compt. 147. W A G E N B B and MCGILL, J. Am.
Bend., 1947, 225, 1371. Pharm. Assoc, 1925, 14, 288.
113. NAKAJIMA and K U B O T A , Ber. ges. 148. MABQUIS, Z. anal. Chem., 1899, 3 8 ,
physiol. expt. Pharmacol., 1927,40, 467.
850. 149. Pharm. Zentralhalle, 1896, 3 7 ,
114. GOHLICH, Arch. Pharm., 1895, 2 3 3 , 844.
261. 150. E L I A S , Pharm. Ztg., 1901, 46, 394.
] 15. D o r a , Pharm. J. Trans., 1888 (3), 18, 151. K O B E E T , Chem. Zent., 1899, ii, 149.
701. 152. GBOVE, Z. anal. Chem., 1874,13, 236.
I 16. H E S S E , Pharm. J. Trans., 1883 (3),18, 153. SIEBOLD, Am. J. Pharm., 1873 (4),
801. 3, 544.
117. K E M P J , J. pr. Chem., 1908 (2), 7 8 , 154. ROSEOTIIALBB, Schweiz. Apoth.-Ztg.,
201. 1923,61, 117.
118. SOHAEUS, Bestimmung der Kristallges. 155. DONATH, J. pr. Chem., 1886 (2), 3 3 ,
in Chem. Lab. erzeugten Prod. 563.
(Wien, 1855). 156. PELLAGBI, Oazz. Chim. Ital., 1877, 7,
III). BROOKE, Ann. Phil., 1823, 22, 118. 297.
120. RAMMELSBEBG, Hanb. Kryst.-Phys. 157. F E S H D E , Z. anal. Chem., 1866, 5, 214.
Chem., 1882, ii. 358. 158. BRTTYLANTS, ibid., 1898, 37, 62.
121. LANO, Silzber. Ahad. Wiss. Wien, 159. E K K E E T , Pharm. Zentralhalle, 1926,
1858,31, 115. 67, 498.
122. DIIKIIIAIIMIO, Ann. CIiAm. l'liys,, 1803 160. MOIUIAHTZA, Bull. Soc Chim. Roy.
(!I), 68, 100. youyodav., J932, 3 , No. 3, 17],
42 MORPHINE AND ITS ISOMERS OH. n
161. E K K E E T , Pharm. Zentralhalle, 1930, 195. ALOY, Bull. Soc. GHm., 1903 (3), 29,
7 1 , 550. 610.
162. R E I C H A B D , Ohem. Ztg., 1904, 2 8 , 196. and RABATJT, Bull. Soc. Chim.,
1102. 1914 (4), 15, 680.
163. TATTEBSAiiL, Ohem. News, 1880, 4 1 , 197. EILOABT, Ohem. News, 1884, 50, 102.
63. 198. MABME.Z.cmaZ.C/teTO., 1885,24, 643.
164. E K K E B T , Pharm. Zentralhalle, 1934, 199. FiUOKiGEB, Arch. Pharm., 1872,201,
75, 50. 111.
165. P B S E Z , J. Pharm. OHm., 1937, 2 5 , 200. REICHABD, Pharm. Zentralhalle, 1906,
504. 47, 247.
166. BBONCINEB, Z. anal. Ohem., 1898, 201. OLIVEB, J. Am. Med. Assoc, 1914,
37, 62. 6 3 , 513.
167. REICHABD, ibid., 1903, 42, 95. 202. Chemist and Druggist, 1914, 8 5 ,
168. P E S B Z , J . P h a r m . GHm., 1938,27,255. 45.
169. E K K E E T , Pharm. Zentralhalle, 1928, 203. N A D L E B , Bull. Soc GHm., 1874 (2),
69, 433. 2 1 , 326.
170. 'Sxs.osASD.Pharm.Ztg., 1004,49,523. 204. Z. anal. Ohem., 1874, 13, 235.
171. V m e i t r s , Arch. Pharm., 1887, 2 2 5 , 205. L I N D O , ibid., 1880, 19, 359.
256. 206. WAOHSMUTH, J. Pharm. BeIg., 1935,
172. E K K E B T , Pharm. Zentralhalle, 1926, 17, 795.
67, 498. 207. SEBTJLLAS, Jahresber. Fortschr. Phys.
173. SCHNEIDEB, Fogg. Ann. der Physih, Wiss., 1831, 11, 238.
1872 (5), 27, 128. 208. LBFOBT, J. Pharm., 1861 (3), 40, 97.
174. J. pr. Ohem., 1873 (2), 6, 455. 209. F U L T O N , J. Lab. GUn. Med., 1928,
175. W E P P E N , Arch. Pharm., 1871, 2 0 5 , 13, 750.
112. 210. GtTABiNO, JBoK. Soc. Ital. Biol. Sper.,
176. FULTON, J. Am. Pharm. Assoc, 1945, 20, 754.
1937, 26, 726. 211. Arch. Sd. Biol, 1946, 3 1 , 115.
177. E K K E B T , Pharm. Zentralhalle, 1928, 212. H A G E B , Pharm. Zentralhalle, 1885,
69, 198. 6, 105.
178. W O R E B a n d A N T E N E B , HeIv. OHm. 213. L E A K B , Proc Soc. Exptl. Biol. Med.,
Acta, 1938, 2 1 , 1345. 1930, 28, 148.
179. B B D M A N N , Ann., 1861, 120, 188. 214. PLtTGOE, Bee. Trav. CHm., 1887, 6,
180. HITSEMANN, ibid., 1863,128, 305. 209.
181. Oot7EBBB, Ann. Chim. Phys., 1835 215. DITTMAB, Ber., 1885, 18, 1612.
(2), 59, 136. 216. JAWOBOSKI,Ohem.Zent.,1896,ii.321.
182. DTTFLOS, J. Ohem. Phys. (Schweigger- 217. HiNTEBBEBGBB, Ann., 1851,77, 201.
Seidel), 1831, 6 1 , 105. 218. CtTMMiNG and BKOWN, J. Soc. Ohem.
183. VAN ITALLIE and STEENHAUEB, Arch. Ind., 1928, 47, 8 4 T .
Pharm., 1928, 265, 696. 219. N O B T H and B B A L , J. Am. Pharm.
184. SANCHEZ, J. Pharm. OHm., 1937,25, Assoc, 1924, 13, 889.
346. 220. BBETBAND, Compt. Rend., 1899, 128,
185. FsAtTDE, Per., 1879, 12, 1558. 743.
186. D A V I D , Pharm. Ztg., 1925, 70, 969. 221. H E I D U S O H K A and WOLF, Schweiz.
187. WIELAND and KAPPELMEIBE, Ann., Apoth. Ztg., 1920, 58, 213, 229.
1911, 382, 306. 222. ROSENTHALEB, Arch. Pharm,., 1927,
188. REIGEL and WILLIAMS, J.A.G.8., 265, 319.
1926, 4 8 , 2871. 223. JOBGENSEN, J. pr. Ohem., 1870 (2),
189. JOBISSEN, Z. anal. Ohem., 1881, 2 0 , 2, 433.
422. 224. BAITEB, Arch. Pharm., 1874,205, 289.
190. FLETIBY, Ann. chim. anal., 1901, 6, 225. D I T T E , Ann. Chim. Phys., 1888 (6),
417. 13, 237.
191. SOHXEK, Arch. Pharm., 1896,234,348. 226. CHBISTBNSEN, J. pr. Ohem., 1892 (2),
192. ABMITACM, Pharm. J. Trans., 1888 45, 356.
(3), 18, 761. 227. VAN U B K , Pharm. Weekblad, 1927,
193. VAN dimr-raN, Pharm. Weckblad, 1932, 64, 371.
69, 000. 228. GLYOABT, J. ASSOC. Official Agr.
104. LAirriHNftrmiiitmim, Arch. Pharm., Ohem,., 1927, 10, 370.
1010,257, IiI. 220. ibid., 1028,11,803.
CH. I I MORPHINE AND ITS ISOMERS 43
230. ROSENTHALER, Am. J. Pharm., 1929, 263. GARRATT, Quart. J. Pharm. Pharma-
101, 821. col., 1937, 10, 466.
231. Mikrochemie, 1934, 16, 37. 264. ADAMSON and H A N D I S Y D E , Analyst,
232. F U L T O N , J. Lab. CUn. Med., 1938, 1945, 70, 305.
23, 622. 265. Quart. J. Pharm. Pharma-
233. W H I T M O R E a n d W O O D , Mikrochemie, col, 1946, 19, 350.
1939, 27, 249. 266. DENOEL, J. Pharm. BeIg., 1946, 1,
234. ibid., 28, 1. 241.
235. OLIVIERIO, Atti. Acad. Gioenia Sci. 267. NICOLINI, Ann. pharm. Franc., 1947,
Nat. Catania, 1938 (6), 3 , 6. 5, 528.
236. and TRTJCOO, ibid. 4 , 15. 268. CRAMER and VOERMAN, Pharm.
237. DUQUENOIS and BUCAK, Rev. faculti. Weekblad, 1949, 84, 129.
sci. Univ. Istanbul, 1950, 5A, 229. 269. W A L T O N and O'BRIEN, Analyst,
238. WACHSMtTTH, Natuurw. Tijdschr., 1931, 56, 714.
1940,22,240. 270. KALLSTROM:, Svensk Farm. Tids.,
239. HERMANN, Biochem. Z., 1912, 39, 1931, 35, 485.
216. 271. DAVID, Pharm. Ztg., 1933, 78, 163.
240. GERMUTH, Am. J. Phdrm., 1927, 99, 272. R A I T H and WISCHO, Pharm.
340. Monatsh., 1932, 13, 125.
241. TREMONTI, Boll. iSoc. Ital. Biol. Sper., 273. KLYACHKINA and SHTUBEB, Arch.
1928, 3 , 393. Pharm., 1933, 271, 217.
242. GIOVANNI, Industria Ohimica, 1929, 274. VAN ARKEL, Pharm. Weekblad, 1935,
4, 458. 72, 366.
243. BAMBORD, Analyst, 1931, 56, 586. 275. IONESOU-MATIU, J. Pharm. Ghim.,
244. SHBMYAKIN, Gompt. Rend. Acad. Sci. 1926 (8), 4, 533.
U.S.S.R., 1937, 14, 115. 276. . Mon. Prod. CUm., 11, No. 109,1.
245. ESPINOS, Ann. m6d. legale criminol. 277. Ghimie et Industrie, May 1927,
police sci., 1927, 7, 231. 174.
246. ROSENTHALER, Mikrochemie JEmich 278. B B I N D L B , Pharm. J., 1927, 119, 608.
Festschr., 1930, 254. 279. VAN ITALLIE and STEENHAUER,
247. D I E T E R I C H , Z. anal. GUm., 1890, 2 9 , Arch. Pharmi, 1928, 265, 698.
484. 280. E D E R and MARKI, Pharm. Ada HeIv.,
248. P APE, Apoth. Ztg., 1909, 24, 70. 1927.2, 21, 41, 70.
249. H E I K E L , Ghem. Ztg., 1908, 32, 1149, 281. MAORI, Boll. CHm. Farm., 1928, 67,
1162, 1212. 129.
250. IONESCU-MATIU, J. Pharm. GMm., 282. BALLS and W O L E E , J. Biol. Chem.,
1926 (8), 4, 533. 1928, 80, 379.
251. PRESCOTT and GARDIN, J.A.G.S., 283. SCHOLTZ, Ber. XJngar. pharm. Qes.,
1898, 20, 706. 1927.3, 379.
252. K E I I I E S , Ann., 1857, 103, 274. 284. D A V I D , ibid., 1926, 2, 103.
253. STEIN, Arch. Pharm., 1871, 148, 150. 285. MARICQ, Bull. Soc. Chim. BeIg., 1929,
254. MILLER, Pharm. J. Trans., 1871 (3), 38, 426, 265.
2, 465. 286. H O L S T and KAHLENBERG, J. Am.
255. H E I D U S C H K A and FAUL, Arch. Pharm. Assoc, 1931, 20, 11.
Pharm., 1917, 255, 172. 287. GOLOD, Anales assoc.guim. Argentina,
250. VAN I T A L L I E a n d HARMSMA, Ghem. 1936, 24, 166.
Zent., 1926, i. 2612; Ghem. Abs., 288. NIOHOLLS, Analyst, 1937, 62, 440.
1927,21, 3703. 289. B A U E R and H I L D E B R A N D T , Pharm.
257. HoffMANN a n d POPOVICI, Pharm. Zentralhalle, 1937,78, 341.
Zentralhalle, 1935, 76, 346. 290. KOEPMSL, Suddeut. Apoth.-Ztg., 1938,
258. VAN ARKEL, Pharm. Weekblad, 1937, 78, 251.
74, 134. 291. FicHTENBERa and LEVY, Compt.
259. GOIN, Anales farm, bioquim. (Buenos Rend. Soc. Biol., 1939, 130, 312.
Aires), 1934, 5, 93. 292. J U U L , Arch. Intern. Pharmacodyna-
200. !DIMICERT, Z. anal. Chem., 1938, 112, mie, 1939, 62, 69.
2*11. 293. MOODEY a n d EMERSON, Univ. Calif.
Ii(II. DAVID, Pharm. Ztg., 193), 76, 706. Pub. Pharmacol., 1939,1, 235.
2(12. HANUTiras1;, Scmana Mid. [Buenos 294. CAT-TEN and F E U E R , Gompt. Rend.,
Airw), ] 030, ii. 333. 1030,208, 1907.
44 MORPHINE AND ITS ISOMERS OH. I I
295. POETHKE, Arch. Pharm., 1940, 278, 325. E D E B and WACKEBLIN, Quart. J.
109. Pharmacol., 1937, 10, 680.
296. E N D O and K A T O , Proc. Jap. Pharma- 326. Committeo Report. Bull. Health Org.
col. Soc., 1938, 12, 136. League of Nations, 1938, 7, 429.
297. MANNICH, Arch. Pharm., 1941, 279, 327. LATJBENOE and LABABRE, Merck's
388. Kept., 1940, 4, No. 4, 8.
298. BAGGBSGAABD-RASMUSSEN, HAHN, 328. NOBILI, Boll. GHm. Farm., 1940, 79,
and ILVEB, Dansk Tids. Farm., 218.
1945, 19, 41. 329. E D E B and WACKEBLIN, Pharm. Acta
299. SHIDEMAN a n d K E L L Y , Science, 1947, HeIv., 1940, 15, 227.
106, 298. 330. MANNICH, Arch. Pharm., 1942, 280,
300. IONESOU-MATIU, Ann. pharm. Franc., 386.
1948, 6, 26. 331. J A N O T and TRISTANT, Bull. Sci.
301. JINDBA, J. Pharm. Pharmacol., 1949, Pharmacol., 1942, 49, 74.
1, 87. 332. TAYLOB, Allen's Comm'l. Org. Anal.,
302. L E G E B , Bull. Sci. Pharmacol., 1938, 1912, vi. 383.
4 5 , 193. 333. SCHMIDT, Abderhalden's Hanb. biol.
303. ITIKAWA a n d Pro, J. Pharm. Soc. Arbeitsmethoden, 1920 9, 449.
Japan, 1937,57, 411. 334. CHOULANT, Gilbert's Ann. der Physik,
304. VAN A B K B L and VAN D E B W I E L E N , 1817, 56, 342.
Pharm. Weekblad, 1931,68, 309. 335. ibid., 1818, 59, 412.
305. S H T U B E R and K L Y A C H K I N A , Arch. 336. LIBBIG, Pogg. Ann. der Physik, 1831,
Pharm., 1930, 268, 209. 2 1 , 1.
306. BONHOUBE, J. Pharm. Ohim., 1929 337. Ann. Ohim.Phys., 1831 (2), 4 7 ,
(8), 10, 442. 147.
307. RUSTING, Pharm. Weekblad, 1931,68, 338. REGNATJLT, ibid., 1838 (2), 68, 113.
767. 339. Ann., 1838,26, 10.
308. ibid., 1932, 69, 433. 340. DUMAS a n d P E L L B T I E B , Ann. Ohim.
309. ibid., 1934, 7 1 , 333. Phys., 1823 (2), 24, 163
310. RBIMBBS, Dansk Tids. Farm., 1930, 341. P E L L E T I E R and CAVENTON, ibid.,
4, 230. 1819 (2), 12, 113.
311. Arch. Pharm., 1931, 269, 506. 342. LAUBENT, ibid., 1847 (3), 19, 359.
312. E D E B and STUCKi.jP/Mmro. Acta HeIv., 343. RAOULT, ibid., 1884 (6), 2 , 66.
1932, 7, 259. 344. EYKMAN,,Z.phys. Ghem., 1888,2, 964.
313. K E Y , QvAm. e ind., 1932, 9, 265. 345. VON KLOBUKOW, ibid., 1889, 3 , 476.
314. VANITAIILIE, JPAaTW. Weekblad, 1934, 346. BEBTBAND and M E Y E B , Ann. Ohim.
71,4. Phys., 1909 (8), 17, 501.
315. MANNICH, Arch. Pharm., 1935, 273, 347. H o w , Ann., 1853, 88, 336.
27. 348. BBOOOKMANN a n d POLSTORFF, Ber.,
316. BAGGESGAABD-RASMUSSEN and R E I - 1880, 13, 96.
MEBS, Dansk Tids. Farm., 1935, 9, 349. H E S S E , Ann., 1883,222, 203.
229. 350. R K I D B L A K T . - G E S . , D. B.-P. 165,898
317. JACKEBOTT a n d J E S P E K S E N , Pharm. (1904); Frdl. 8, 1153; Houben, 2 ,
Acta HeIv., 1936, 11, 307. 519.
318. R O S I N a n d W I L L I A M S , J. Am. Pharm. 351. D. n.-P. 166,362 (1904); Frdl. 8,
Assoc, 1935, 24, 1053. 1155; Houben, 2 , 529.
319. WALLINGFORD and H O H E Y E B , ibid., 352. D. R.-P. 191,088 (1906); Frdl. 8,
1936, 2 5 , 402. 1154; Houben, 2, 882.
320. KtrAMX-Lsafz, Pharm. Monatsh., 353. GEBBEB, D. R.-P. 228,246, (1909);
1937, 18, 17. Frdl. 10, 1211; Houben, 3 , 497.
321. LEGEB, Bull. Sci. Pharmacol., 1937, 354. H E B Z I G and M E Y E B , Monatsh., 1897,
44, 214, 366. 18, 379.
322. DOWZABD, THOMAS, and Rtrsso, J. 355. OHABBIEB and N E B I , Gazz. Ohim.
Am. Pharm. Assoc, 1937, 26, 015. ltal., 1929, 59, 804.
323. BAaaiasaAARD-RASMUssuiN and Jiss- 356. ibid., 1931,61, 604.
I'IOUHIIIN, Dansk Tids. Farm., 1937, 357. R O Y , ./. Indian Oham. Soc, 1941, 18,
11,278. 20.
i)2'l. CJOUTINIIO,,/. I'lutm. IM1/., !0!!7( 19, II5H. (JjtiMAUx, (Umipt. Ht'iid., 1881, 9 2 ,
047, 001, 070. IUO.
CH, I I MORPHINE AND ITS ISOMERS 45
359. GBIMAUX, Oompt. Rend., 1881, 92, 391. K A U D E B , U.S. Pat. 623,789 (1899).
1228. 392. U.S. Pat. 626,910 (1899).
360. ibid. 9 3 , 67. 393. TSCHITSOHIBABIN and KussANomr,
361. ibid. 9 3 , 217. .BMZZ.SOC.CTMTO., 1927 (4),41,1649.
362. ibid. 9 3 , 591. 394. CARLSON and CBETOHEB, J.A.G.S.,
363. Pharm. J. Trans., 1881 (3), 12, 1948, 70, 2284.
48. 395. F O L D I , Ber., 1920, 5 3 , 1839.
364. K N O L L and Co., D. B.-P. 39,887 396. MANNICH, D. B.-P. 280,972 (1913);
(1886); Frdl. 1, 582; Houben, 1, Frdl. 12, 740; Houben, 4, 431.
711. 397. J. Soc. Ghem. Ind., 1915, 34,
365. Arch. Pharm., 1889, 227, 229. 452.
366. GEBBEB, D. B.-P. 214,783 (1908); 398. Apoth.-Ztg., 1915, 30, 56.
Frdl. 9, 1020; Houben, 3 , 296. 399. Arch. Pharm., 1916, 254, 349.
367. MBECK and Co., D. B.-P. 102,634 400. SCHNBEGANS, J. Pharm. Elsass-
(1898); Frdl. 5, 807; Houben, 1,711. Lothr., 1897, 3.
368. D. B.-P. 107,225 (1898); Frdl. 5, 401. Pharm. Ztg., 1897,42, 248.
808; Houben, 1, 776. 402. EMEESON, KLYZA, PHATAK, and
369. D. B.-P. 108,015 (1898); Frdl. 5, LEAKE, Univ. Calif. Pub. Pharma-
808; Houben, 1, 787. col, 1938, 1, 59.
370. D.B.-P. 131,980(1901); Frdl.b, 403. COHN, Monatsh., 1898, 19, 106.
1156; Houben, 2, 177. 404. VON K B K E S Z T Y and W O L F , D. R.-P.
371. D. R.-P. 418,391 (1923); Frdl. 343,055 (1919); Frdl. 13, 879;
15, 1515. Houben, 5, 331.
372. F A B B E N F A B . VOBM. F . BAYEB and 405. K N O L L and Co., D. R.-P. 116,806
Co.,D.R.-P. 92,789 (1896); Frdl. 4, (1900); Frdl. 6, 1157; Houben, 1,
1247; Houben, 1, 528. 882.
373. D. R.-P. 96,145 (1897); Frdl. 5, 406. D. R.-P. 38,729 (1886); Frdl. 1,
806; Houben, 1, 595. 582; Houben, 1, 53.
374. D. R.-P. 95,644 (1897); Frdl. 5, 407. OTTO and HOLST, Arch. Pharm.,
805 -,Houben, 1, 585. 1891,229, 618.
375. >. .R.-P. 189,843 (1906); Frdl. 8, 408. MEBOK, D. B.-P. 106,718 (1899);
1151; Houben, 2, 876. Frdl. 5, 809; Houben, 1, 774.
376. D. R.-P. 224,388 (1909); .Frd?. 409. M E N N E L , U.S. Pat. 650,408 (29 May
10, 1216; Houben, 3 , 780. 1900).
377. BOEHBINGEK-SOHN, D. JJ.-P. 247,180 410. R E U T E B , U.S.Pat. 842,011 (1907).
(1909); Frdl. 10, 1215; Houben, 3 , 411. E M D B , Apoth.-Ztg., 1932,47, 349.
780. 412. CHASTAING, Rip. Pharm. J. CHm.
378. RODIONOV, BwJJ. SOC. CHm., 1926 mid., 1881, 9, 15.
(4), 39, 304. 413. ibid. 86.
379. ibid., 1929 (4), 4 5 , 109. 414. Pharm. J. Trans., 1881 (3), 12,
380. and VVEDBNSKII, J. Ghem. Ind. 47.
U.S.S.B., 1930,7, 11. 415. . J . Pharm., 1881 (5), 4, 19.
381. CHEMNITTUS, Pharm. Zentralhalle, 416. RAKSHIT, J.C.S., 1918, 466.
1927, 70, 101. 417. MANOINI, Chim. ind. agr. biol., 1932,
382. AKTZ, O-VA. P B O . T O B . K H I M . - 8, 411.
F A B M . P E E P . M E D . I M . , BUSS. Pat. 418. W E I G H T , J.G.S., 1874, 1031.
18,224 (18 J u l y 1927). 419. TIIWENEATT, Bull. Soc. GHm., 1915
383. SHAPOSHNIKOV, Russ. Pat. 50,438. (4), 17, 109.
384. TBAUB, U.S. Pat. 1,100,998 (23 J u n e 420. DANOKWOKTT, Arch. Pharm., 1890,
1914). 228, 572.
385. GBIMAUX, J. Pharm., 1881 (5), 4, 17. 421. PiSOHEE, D. B.-P. 622,231 (1934);
386. Ann. GHm. Phys., 1882 (5), Frdl. 22, 584.
27, 273. 422. RIZZOTTI, Arch. Intern. Pharmaco-
387. M.TSB.G-K, Arch. Pharm., 1899,237, 211. dynamic, 1935, 52, 87.
388. H E S S E , Pharm. Zentralhalle, 1899, 423. Atti Soc. Medchir. Padova, 1935,
40, 1. 13, 12.
380. Mmnma, U.S. Pat. 629,264 (1899). 424. Ber. Cfes. physiol. exptl. Phar-
31)0. HiiwoNnmua, U.S. Pat. 629,433 mahol., 1935,89, 189.
(IHUI)). 425. WiuuuT, Science, 1040, 92, 244.
46 MORPHINE AND ITS ISOMERS OH. II
560. VONGEBICHTEN and SCHBOTTEB, 593. L E R O Y , Ann. GMm. Phys., 1900 (7),
ibid., 1882, 15, 1484. 2 1 , 87.
361. Ann., 1881,210, 396. 594. HARTLEY, Phil. Trans. Roy. Soc,
562. Ber., 1901, 34, 767. 1885, 176, 471.
563. ibid. 1162. 595. MAYEB, Arch. Pharm., 1878,213,413.
564. W E B T H B I M , Ann., 1850, 7 3 , 208. 596. KITASATO, Acta Phytochim., 1927, 3 ,
565. SKBAUP and W E I G M A N N , Monatsh., 175.
1889, 10, 101. 597. BRUSTIEB, Bull. Soc. GHm., 1926
566. F A E B W E B K E VOBM. M E I S T E B L U C I U S (4), 39, 1527.
UND BBtNiNG, D. B.-P. 90,207 598. STEINEB, Bull. Soc. Chim. Biol., 1924,
(1896); Frdl. 4 , 1247; Houben, 1, 6, 231.
475. 599. GOMPEL and H E N R I , Gompt. Rend.,
567. SCHMIDT, Ber., 1875, 8, 1274. 1913, 157, 1422.
568. F R E U N D , ibid., 1905, 38, 3234. 600. GiRAEDET, J.O.S., 1931, 2630.
569. GADMEB and KNOCK, Arch. Pharm., 601. B B U S T I E B and BLANC, Bull. Soc.
1921, 259, 135. Chim., 1934 (5), 1, 702.
570. Soc. ANON. I N D . CHIM. A BALE, 602. BEGUIRISTAN, Chem. Abs., 1943, 3 7 ,
Swiss Pat. 78,905 (1918). 3560.
571. Swiss Pat. 78,913 (1918). 603. SMALL and RAPOPORT, J. Org. Chem.,
572. Swiss Pat. 76,996 (1918). 1947, 12, 284.
573. G E S . E U B C H E M . I N D . I N BASEL, 604. FITCH, and SMITH, J.A.G.S.,
D. R.-P. 322,335 (1916); Frdl. 1936, 58, 1457.
13, 875; Houben,5, 148. 605. TUBNBULL, and F I T C H , J. Org.
574. D. R.-P. 330,814 (1917); Frdl. Chem., 1938, 3 , 204.
13, 878; Houben, 5, 210. 606. MANNICH and SOHULTE, Arch.
575. HTJSSY and FOHRENBACH, U.S. Pat. Pharm., 1938, 276, 593.
1,255,423 (1918). 607. SMALL, J. Org. Chem., 1947, 12, 359.
576. BOEHBINGEB-SOHN, D. R.-P. 254,502 608. E M D E , HeIv. Chim. Acta, 1930, 13,
(1911); Frdl. 11, 993. 1035.
577. D. R.-P. 270,575 (1912); Frdl. 609. SCHBYVER and L E E S , J.C.S., 1901,
11, 995. 563.
578. STBAXTB, U.S. Pat. 1,061,139 (1913). 610. L E E S and TUTIN, Proc. Chem. Soc,
579. Schweiz. Wochschr., 1912, 50, 1906, 22, 253.
459. 611. K N O B B a n d H O B L E I N , Ber., 1907, 4 0 ,
580. H U G , U.S. Pat. 1,069,954 (12 Aug. 3889.
1913). 612. SMALL and F A R I S , J.A.G.S., 1935,
581. DOTT, Pharm. J. Trans., 1921, 106, 57, 364.
232. 613. ibid., 1934,56, 1930.
582. B R U N E I and OLIVIEBO, Gompt. Rend., 614. LUTZ a n d SMALL, ibid., 1934, 56,
1941,212, 579. 2466.
583. DUBLANC je, J. Pharm., 1827 (2), 615. K N O B B and H O B L E I N , Ber., 1907, 4 0 ,
13, 261. 2032.
584. DOTT, Pharm. J. Trans., 1926, 117, 616. SMALL and L U T Z , J.A.C.S., 1934, 56,
760. 1928.
585. H E N R Y fils and PLISSON, J. Pharm., 617. ibid., 1932, 54, 4715.
1828 (2), 14, 241. 618. TAUSCH, Arch. Pharm., 1880, 216,
586. HOOBWEG, Maandblad voor Natuur- 287.
wettenschappen (Amsterdam), No. 1, 619. GOHLICH, ibid., 1895, 233, 631.
3, 12. 620. SCHMIDT, Ber., 1877, 10, 194.
587. MAiBCH,Arch.Pharm.,1871,19b, 118. 621. B A U E E , Arch. Pharm., 1874,205, 289.
588. P B L L E T I E B , J. Pharm., 1823 (2), 9, 622. K U N Z , ibid., 1888, 226, 307.
530. 623. T E M M L E B - W E E K E V E B E I N I G T E C H E M .
589. DEREGIBUS, Ann. Chim. Farm., 1886 FABBIK, D. R.-P. 564,958 (1931);
(4), 3 , 329. Frdl. 19, 1219.
590. Jahresber.Fortschr.Ohem., 1886, 624. ELDERHORST, Ann., 1850, 7 4 , 77.
1705. 625. BODEKEK, ibid., 1849,71, 63.
501. MAYwii, Clan. QlAm. ltal., 1910,40 ii, 620. I-IOITMANN, ROTH, I-IOBOKO, and
402. MWraLUii, IUr., 1910,43, 2024.
802. PWU1IZ1AiIi, Ann., .1888, 248, 140. 027. How, Ohmib. ZuM., 1855, 03.
OH. I I M O R P H I N E AND I T S ISOMERS 49
628. PETTENKOTER, Buchner's Repert 664. N E U B E B G , Ber., 1902, 3 5 , 1473.
Pharmazie, 1855, 4, 45. 665. GTHATAK, Bull. Acad. Sci. United
629. DOLLI-US, Ann., 1848, 6 5 , 212. Provinces Agra, Oudh, Allahabad,
630. W I N K L E R , CUm. Zent., 1851, 145. 1933, 3 , 75.
631. JOBGENSEN, Ber., 1869, 2 , 460. 666. NITRAVATI, D A S S , and D U T T , Proc.
632. CHATTAWAY and P A R K E S , J.G.S., Indian Acad. Sci., 1938, 8A, 145.
1930, 1003. 667. M E R C I E S and DETRIE, J. Pharm.
633. L I B B I G , Ann., 1838, 26, 4 1 . GHm., 1940 (9), 1, 287.
634. SOHWABZENBACH, Jahresber. Fortschr. 668. BEBLINGOZZI and BENIGUI, Ann.
GUm., 1859, 393. GHm. Farm., August 1938, 7.
635. FBANgois and BLANC, Gonvpt. Rend., 669. DEL TANAGO, Anales real. acad. farm.,
1922, 175, 169. 1943, 9, 235.
636. Bull. Soc. GMm., 1922 (4), 670. SHA, M A , and H o o , Sci. Repts. Natl.
3 1 , 1208. Tsinghau Univ., [A] 1934, 2 , 245.
637. ibid. 1304. 671. WASSERMANN, Ann., 1932, 492,
638. GROVES, GUm. Zent., 1858, 890. 266.
639. THOMSEN, CUm. Aba., 1911, 5, 3417; 672. I . G. FARBENINDUSTRIE A K T . - G E S . ,
CUm. Zent, 1911, i, 1515. D. R.-P. 504,681 (1927); Frdl. 17,
640. FRANCOIS and BLANC, Bull. Soc. 2624.
GHm., 1923 (4), 33, 640. 673. K H A L E S T S K I I and GERSHENTSVIT,
641. W I L K E - D O B F U B T and BALZ, Ber., J. Gen. GUm. (U.S.S.R.), 1947,
1927,60, 115. 17, 2066.
642. L A N G E a n d M U L L E R , ibid., 1930, 6 3 , 674. M C A L I S T E B and KENNER, J.G.S.,
1058. 1928, 913.
643. ibid., 1929,62, 786. 675. TROGE and L I N D E , Arch. Pharm.,
644. J A N O T and CHAIGENEATT, Compt. 1901,239, 131.
Bend., 1949,228, 1152. 676. SCHAEEER, J. Soc. CUm. Ind., 1910,
645. DITZLER, Arch. Pharm., 1886 (3), 24, 29, 928.
701. 677. MAXWELL and ADAMS, J.A.C.S.,
646. BEOKUBTS, ibid., 1890, 228, 347. 1930, 52, 2959.
647. OTTDEMANS, Arm., 1873, 166, 65. 678. STEELE and ADAMS, ibid. 4528.
648. WILHELMY, Pogg. Ann. der Physik, 679. I . G. FARBENINDUSTRIE AKT.-GES.,
1850 (3), 2 1 , 527. Brit. Pat. 452,868 (1 Sept. 1936).
649. FLORENCE, Bull. Soc. GHm., 1927 680. D. R.-P. 644,647 (1937); Frdl.
(4), 4 1 , 1097. 22, 553.
650. ALBERT, Australian J. Pharm., 1933, 681. O W E N and SIMONSEN, J.C.S., 1933,
14, 442. 1223.
651. DOTT, Pharm. J. Trans., 1881 (3), 682. MILLS and B A I N , ibid., 1910, 1866.
11, 618. 683. D O H N and DIEDBIOH, U.S. Pat.
652. E H B L I C H a n d SCHTTBEET, Ber., 1929, 2,411,495 (19 Nov. 1946).
62, 1974. 684. I . G. FARBENINDUSTRIE A K T . - G E S . ,
653. LisiTZum, Biochem. Z., 1933,266,25. JD. R.-P. 536,276 (1930); Frdl. 18,
654. STARK and D E H N , J.A.C.S., 1918, 2874.
40, 1573. 685. GRAFINGHOFF, Zeitschr. Chem., 1865,
(155. DOTT, Pharm. J. Trans., 1886 (3), 8, 599.
16, 958. 686. E D D Y , J. Pharmacol, 1933, 49, 319.
(156. M O K E N Z I E , J.C.S., 1899, 969. 687. Merck's Index, Merck and Co., 6th
(157. DTTBLANC, Ann., 1832, 3 , 121. edn. (Rahway, N.J.), 1940.
(158. GOBEL, Buchner's Repert Pharmazie, 688. MANNICH AND S I E W E R T , Arch.
11, 83. Pharm., 1939, 277, 128.
(159. KARMRODT, Ann., 1852, 8 1 , 171. 689. E D D Y , J. Pharmacol., 1935, 5 5 , 127.
(160. MAPLETIIORPE and E V E R S , Pharm. J. 690. BRETEAU, J. pharm. GHm., 1927 (7),
Trans., 1925, 115, 137. 5, 473.
(HII. IONESCU-MATIU and ILIESCO, J. 691. THOMSON, Pharm. J. Trans., 1920,
Pharm. CMm., 1936 (7), 23, 117. 104, 7.
(102. ARBPE, J. pr. CUm., 1851 (1), 5 3 , 692. VONGEBICHTBNand SCHBOTTER, Ber.,
,Til. 1882, 15, 2179.
(KCI. I'AMTUUU, Ann. GMm, Phi/s., 1853 (3), 093. MioiioK, D. R.-P. 91,8)3 (1896); Frdl.
38, .155. 4, 1245.
5447.1 JO
50 M O R P H I N E AND I T S ISOMERS OH. I I
694. MEBING, U.S. Pat. 584,388 (1897). 700. CHEM. F A B B I K VOBM. SANDOZ, U.S.
695. DOTT, Pharm. J. Trans., 1925, 117, Pat. 1,892,019 (27 Deo. 1933).
757. 701. K A B B E B and HEYNEMANN, HeIv.
696. Chemist and Druggist, 1926, GUm. Acta, 1948, 3 1 , 398.
104, 7. 702. F E B B E I N , Schweiz. Wochschr., 1913,
697. CHEM. F A B B I K VOBM. SANDOZ, Brit. 51, 1.
Pat. 343,397 (1929). 703. E D D Y a n d H O W E S , J. Pharmacol.,
698. D. B.-P. 524,639 (1929); Prdl. 1935, 5 5 , 257.
18, 2872. 704. K A B B B B and WIDMABK, HeIv. Chim.
699. French Pat. 709,789 (1930). Acta, 1951, 34, 34.
Ill
PSEUDOMORPHINE
Iw an investigation of the alkaloids obtained from opium Pelletier [1-3]
reported the isolation of a base, pseudomorphine, t h a t has since been
prepared by the gentle oxidation of morphine under a variety of con-
ditions, especially in alkaline solution. The various agents t h a t effect
the change are:
(a) alkaline potassium ferricyanide [4-8];
(b) mercurous chloride [8];
(c) potassium persulphate, copper, and pyridine [8];
(d) nitrous acid [9-12];
(e) ammoniacal copper [4, 13-14] or silver [4] salts;
(/) potassium permanganate and alkali carbonates [15];
(g) atmospheric oxygen and ammonia [16];
(h) potassium cupricyanide and hydrogen peroxide [17-19];
(i) electrolytic oxidation in dilute sulphuric acid [20];
(j) enzymes present in extracts of russula delica [18, 21-24] and in
gum arabic [25].
(k) Pseudomorphine is also formed in small quantity during the
bromination of morphine with hydrobromic acid and hydrogen
peroxide [26], and
(Z) in the sterilization of solutions of morphine hydrochloride in
sealed tubes [27], but a trace of acid or reducing agent hinders
this change [28].
Of these oxidations (a) and (b) are reported to give yields of 90 per cent.
[8]; (c) 75 per cent. [8]; (K) 20-25 per cent. [17]. I t is not known whether
pseudomorphine is actually present in opium or whether it is formed
from morphine during the process of extraction [29]; the amounts
obtained from this source are in any case very small (about 0-02 per
cent, of opium): the method of extraction is described by Hesse [30].
Pseudomorphine has also been called oxymorphine [10], oxydimorphine
15, 6, 11, 15-16], dehydromorphine [31], and phormin [29].
PHYSICAL PROPERTIES
Pseudomorphine is sparingly soluble in most organic solvents, the
host being benzyl alcohol, pyridine, and guaiacol [19]. The rotatory
power of the hydrochloride has been given as [a\ = 114-76 [32];
l<x]D = 103-13 [31]; 109-6, 107-7 [33] (in water). The rotatory
power of the base in alkali is variable [23], the rotation being the same
52 PSEUDOMOBPHINE CH. I l l
for a given ratio of base: alkali whatever the actual concentrations, and
is determined by the equation ilf(/a/c+10) 0 4 3 5 = a constant, where M
is the rotation, / the activity coefficient of the potassium hydroxide of
molar concentration a, and c is the molar concentration of pseudo-
morphine. The constant is approximately 572 [34].
D E T E C T I O N AND ESTIMATION
The following colour tests have been recorded for the detection of
pseudomorphine.
COMPOSITION
A monomolecular formula C 17 H 18 O 4 N was first postulated for pseudo-
morphine [30], the dimolecular (C 17 H 18 O 3 N) 2 being later suggested by
Broockmann and Polstorff [11] on the grounds that nitric oxide is
ovolvocl when morphino hydrochloride is oxidized by silver nitrite,
though thiH waH quest ionod by Hosso |12]. Tho dirnolocular compo-
sition wan finally verified by tho oxidation of morphino with an
OH. I l l PSEUDOMORPHINE 53
equimolecular quantity of potassium ferricyanide, when pseudo-
morphine resulted in 70-88 per cent, yield according to the equation
2C 1 7 H 1 9 O 3 N+ 2KOH+2K 3 Fe(CJST) 6
= (C l 7 H 1 8 0 3 N) 2 +2K 4 Fe(CN) 6 +2H 2 0. [6-7]
The formula was later confirmed by molecular weight determination
[33, 45-46].
STRUCTURE
Concerning the structure of pseudomorphine little is known with
certainty. The two morphine units were originally believed to be
joined in the 2 : 2 ' positions as this was assumed to be the reactive
position in the morphine molecule [i], and bromomorphine, believed
to have the bromine in position 2, cannot be oxidized in this way [47].
However, the bromine atom in bromomorphine is now known to be in
position 1 [48], which is presumably the most reactive position, and
pseudomorphine may be 1: l'-dimorphine. An attempt to reduce
1-bromomorphine to a dimolecular derivative by heating in alcoholic
alkali with palladium on strontium carbonate and hydrazine (method
of Busch [49]) failed, only amorphous coloured substances being
obtained [50].
Bertrand and Meyer [46], following a study of the optical properties
of pseudomorphine, suggested t h a t in this base the two morphine units
are not symmetrically arranged, and indeed the two halves react
differently. Although a tetra-acetyl derivative can be prepared by
heating the base with acetic anhydride [12] or acetyl chloride [51], only
a monomethyl ether results when the base is treated with methyliodide
and alkali, and this is alkali-insoluble [52], though it can be converted
to a triacetyl- and a tribenzoyl-derivative [52]. A di-methiodide can be
formed b y heating the methyl ether with methyl iodide under pressure
at 110 C , and this is converted to a basic methiodide-methohydroxide
b y ammonia, indicating t h a t the nitrogen atoms differ in some way
152], Also oxidation of morphine methiodide with alkaline potassium
ferricyanide gives pseudomorphine methiodide-methohydroxide, which
yields the di-methiodide on treatment with hydriodic acid [53],
Ooto and Kitasato [54-55] degraded the methiodide-methohydroxide
by heating with sodium acetate and acetic anhydride to what they
claimed was bis-(2:2')-3:4-diacetylmorphol, which they methylated
to ' bis-(2:2')-3:4-dimethylmorphol' (morphol is 3:4-dihydroxyphenan-
throne). At the same time a- and /3-dimetathebainone (prepared by the
HI'Ivor nitrate oxidation of metathebainone [n] and almost certainly
III'H-I : ! ' compounds [54]) wero degraded to what was assumed to be
I)IH-(I; J')-3-mothyl-4-aoo1<ylmor[)hoI [54-55], but the crucial hydrolysis
54 PSEUDOMORPHINE OH. HI
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Refs.
Tctrahydro-y-pseudomorphine sul-
phate . . . . . H2O + 20-9 H2O 56
Octahydro-y-pseudomorphine . 56
dihydrochloride . . . . H2O + 8-9 25 H2O 56
dihydrobromide. H2O + 8-2 23 H2O 56
diperchlorate . . . . H2O + 6-3 23 H2O 56
Morphine-y-isomorphine . 268-269 NH 1 OH -26-4 24 JV-HOl 56
TotrahydrodidesoxyBseudomorphme
2XI1O 818 -13-4 27 N -HCl 56
ISOLATION
Codeine may be isolated from opium by the 'Gregory process' [9],
in which the concentrated aqueous opium extract is treated with a
concentrated solution of calcium chloride, when calcium meconate,
lactate, and sulphate are precipitated and removed, when the filtrate
on concentration deposits the 'Gregory salt', a mixture of the hydro-
chlorides of morphine and codeine. This is purified, dissolved in water,
and the morphine precipitated by ammonia, when the codeine remains
in solution from which it is extracted by benzene, or the solution
concentrated to the point at which a mixture of codeine hydrochloride
and ammonium chloride separates. Other procedures for the isolation
of codeine are available [7, 8, 10-22 inc.], critical summaries of which
are given by Kanewskaja [23] and Barbier [24]. Codeine may be
separated from neopine (see Chap. VII) through the sulphate [25] and
from morphine by chromatography [26-29]. Most of the codeine used
commercially is prepared by the methylation of morphine (see below).
PHYSICAL PROPERTIES
Crystallized from ether or benzene codeine is obtained as prisms,
from water or aqueous alcohol as rhombic prisms (hydrated) [30] or
octahedra [31], and as rhombohedra from carbon disulphide. Gaubert
[32] claimed t h a t above 60 C. it crystallizes as rhombic hemihedra,
but below 60 C. as four kinds of spherulites, but the cooling curve
gives no evidence of the existence of the latter four forms [33]. The
liydratod base offloroscos to somo extent and melts under boiling water.
58 CODEINE AND ITS ISOMERS CH. IV
DETECTION
The following colour tests for codeine have been recorded.
Reagent Colour References
,, 150 0.
couo. H 2 SO 1 -^FeCl 2 blue > dirty green 73-75
cone. H 2 S 0 4 + c o n c . HNO 3 pale green > violet-green 76
cone. H 2 S 0 4 + K R e 0 4 yellow-green * violet 77
cone. H 2 SO 4 -)-p-dimethylaminobenzalde- blood red 78
hyde
Na0H
cone. H 2 SO 4 +sodium arsenite green or ui
blue n
> yellow 79-80
cone. H 2 SO 4 + ammonium selenite brilliant green 81-82
cone. H 2 S O 4 + 3 0 % H - C H O red-violet > blue-violet 83-85
cone. H 2 S 0 4 + s o d i u m arsenate dark blue 86
cone. H 2 S O 4 + 1 0 % KBr, 100 C. yellow - brown > green 87
cone. H 2 S 0 4 + a m m o m u m molybdate green > red-brown 88
cone. H 2 SO 4 +(NH 4 ) 2 S 2 0 8 orange 88
cone. H 2 SO 4 +benzidine yellow * brown > dark green 89
cone. H a S 0 4 + b e n z i d i n e add to water violet (extracted b y CHCl3) 89
cone. HS0 4 +NaOCl solution Bky-blue 90
cone. H 8 S 0 4 + a m m o n i u m uranate blue 91
mannitol oxidizod b y Br/H a O then violet-rose 92
oono. H 9 SO 4
moiMton with oono, minroMo goluUon, thou piivplor> W)(I 9,1-94
add oono. Hi)SiO4
OH. IV CODEINE 59
Colour tests are also given by Fulton [106]. Precipitation tests are given
by references [107-14 inc.], microprecipitation tests by references
[5, 114-20 inc.], and other methods of detection and identification of
codeine b y references [121-42 inc.].
ESTIMATION
Codeine has been estimated by volumetric titration with mercuric
salts [143-5], potentiometric methods [146-7], iodimetrically [148],
colorimetrically [149], as silico-tungstate [150] and in other ways
[29, 42, 151-9 inc.].
COMPOSITION
Numerous empirical formulae were initially suggested for codeine
[76, 160-4], the correct composition corresponding to C 18 H 21 O 3 N-H 3 O
for the hydrated base finally being determined by Gerhardt [165-6] and
Anderson [167-8]. I t was subsequently suggested b y Wright [169-70]
that the formula be doubled, but no necessity for this has ever been
revealed.
Codeine is a tertiary base, readily forming quaternary salts [171-7
inc.], t h a t with ethylene dibromide being dimolecular [172-3]. The
molecule also contains one alcoholic group and one methoxyl group,
and was eventually recognized as the methyl ether of morphine [178-
80], as was finally proved by Grimaux [181-6] and by Hesse [187].
P R E P A R A T I O N FROM MORPHINE
Most of the codeine used commercially is prepared by the methylation
of morphine, for which the following methods have been used :
(a) Methylation of morphine or its alkali salts by salts of methyl-
sulphuric acid [188-9].
(b) Methylation with methyl sulphite and alkali [190].
(c) Methylation with sodium alkoxides and methyl sulphate [191].
(d) Methylation with sodium methoxide and trimethylphosphate
[192], methyl nitrite [193], or methyl esters of sulphonic acids
[194].
60 CODEINE AND ITS ISOMEKS CH. IV
D EMBTH YL ATION
Codeine cannot be demethylated to morphine chemically.']" If it is
heated with hydriodic acid no methyl iodide is evolved [169, 209-11],
but the latter is evolved copiously when codeine is heated with hydriodic
acid and red phosphorus [169, 211-212], tbo other products being intrac-
table, varnish-like substances obtainable in the same way from mor-
phine [213] and supposed to consist of polymers of morphine and
codeine. These so-called polymers were also obtained during the action
of hydrochloric and hydrobromic acids on the bases, and were the sub-
ject of an inconclusive series of investigations by Wright [169, 170,
213-14 inc.]. There is no real evidence for the existence of the polymers.
Biological demethylation of codeine by various enzymes and by the
glycerol extract of the mould Polyporus hispidus in nine to twelve days
at 25-37 C. has been reported [225].
ESTERS
The alcoholic hydroxyl group of codeine can be acetylated by glacial
acetic acid or acetic anhydride [226] to give acetylcodeine, the nitrogen
ring being stable [227]. Numerous other esters have been prepared
1223, 228-33].
THE HALOGENOCODIDES
When codeine [i] [234] is heated with concentrated hydrochloric acid
[235-6], treated with phosphorus pentachloride and/or oxychloride
[237] or thionyl chloride [238-40], the hydroxy] group is replaced by
olilorino and a-ohlorooodido [ n | is formod. Tho structure of this has
|- TIIIH IHIM now boon uoooinjillHliod MOO Oluip. X X V I I .
OH. IV CODEINE 61
APOCODEINE
Apocodeine [vin], the 3-methylether of apomorphine, is formed when
codeine is heated with zinc chloride [209-10, 219, 225], anhydrous
oxalic acid [256-9], or phosphoric acid [240]. (Cf. the preparation of
apomorphine from morphine, Chapters I I and XXII.) A substance
given the name apocodeine was prepared by treating bromo- and a-
chlorooodidos with alkalino reagents [172, 260], but this is not an ana-
logue of apomorphine and is probably a complex: mixture [26I].
62 C O D E I N E AND I T S ISOMERS OH. IV
R E D U C T I O N OF C O D E I N E
(a) Catalytic hydrogenation of codeine proceeds rapidly with satura-
tion of the 7:8 double bond and formation of dihydrocodeine [in,
R = OH] [267-9], also obtainable by the electrolytic reduction of
codeine [270], the catalytic reduction of neopine [xin] [271], the methy-
lation of dihydromorphine [272], and the catalytic reduction of dihydro-
codeinone [xiv] [273]. B y the latter method the optical antipode of
dihydrocodeine may be prepared from the sinomenine series [274-5]
(see Chap. X X V I I ) . Both enantiomorphs can be demethylated to the
corresponding dihydromorphines [269, 274-5]. Dihydrocodeine methyl
ether is identical with tetrahydrothebaine [276-8] (see Chap. X I I I ) .
(b) Reduction of codeine with sodium and alcohol was reported to be
ineffective by Vongerichten [279], b u t Knorr in this way obtained high-
melting phenolic substances t h a t he believed to be dimolecular [280].
Codeine is an allylic alcohol, and sodium and alcohol reduction could
prooeed b y elimination of the alcoholic group to give desoxycodeine-C
[xv], whioh is known to bo roduoed in this way to a mixturo of dihydro-
dosoxyoodoino-B [xvi] and dihydrodosoxyoodoino-O [xvu] [248, 281].
CH. IV CODEINE 63
AcO
OAc
JTMe2
HO-
[XXIX] [XXX] [XXXI] [XXXII]
CATALYTIC REARRANGEMENT
Codeine [i] on heating in alcohol with [319-23] or without [324] acid,
with [319-21] or without [322-4] hydrogen, in the presence of noble
metal catalysts, undergoes rearrangement to dihydrocodeinone [xiv].
The yields claimed for the transformation are up to 95 per cent. [323],
b u t Rapoport [304] was unable to obtain yields in excess of 50 per cent.
Thebainone-A [xxxvii] is a by-product in this reaction, and can be
made the main product b y modifying the conditions [325] (cf. the con-
version of codeine methyl ether to thebainone-A enol methyl ether by
sodium ethoxide).
C O D E I N E - N - O x i D E AKD ITS D E R I V A T I V E S
Like other tertiary amines, on heating with 30 per cent, hydrogen
peroxide codeine is converted to an N-oxide; this is reduced to codeine
by sulphurous acid [348]. A dimolecular oxide C36H44O9N2 7H2O is
obtained from the not too prolonged treatment of the base with 1-5 per
cent, hydrogen peroxide on the water-bath; it is transformed to a
monomolecular oxide by heating with alcohol and concentrated hydro-
chloric acid [349].
When codeine-N-oxide is sulphonated, two isomeric codeine-N-oxide
sulphonic acids, a- and /J-, are obtained; the former being transformed
to the latter by alkali. Both yield the same codeine sulphonic acid
on reduction with sulphurous acid, a- and /3-Codeine-N-oxide sulphonic
acids and codeine sulphonic acid are converted to codeine by super-
heated steam and to jS- and y-codeine sulphonic acids by cold con-
centrated sulphuric acid [339, 350].
Nitration of codeine sulphonic acid affords 1-nitrocodeine [339, 350],
whilst nitration and sulphurous acid reduction of a-codeine-N-oxide
sulphonic acid gives a-nitrocodeine, which can be reduced to 1-amino-
codeine [339, 350, 341]. Bromination of the a-N-oxide sulphonic acid
gives a perbromide of unknown constitution [339, 350] that is reduced
to 'bromocodeine dibromide' C18H20O3NBr3 [295].
Catalytic reduction of a-codeine-N-oxide sulphonic acid affords <x-
dihydrocodeine sulphonic acid, which with water at 100 C. gives
dihydrocodeine, and with nitric acid gives 1-nitrodihydrocodeine.
Catalytic reduction of /3-codeine-N-oxide sulphonic acid and of codeine
sulphonic acid gives /3-dihydrocodeine sulphonic acid, which gives the
same products as the a-isomer with superheated steam and with nitric
acid [341]. Dihydrocodeine-N-oxide gives only one sulphonic acid
[295, 341], and this is reduced by sulphurous acid to /3-dihydrocodeine
sulphonic acid [341]. With bromine the N-oxide sulphonic acid gives a
substance C18H22NO3Br, presumably 1-bromodihydrocodeine [295].
MeO,
RO
[XLVI] [XLVII] [XLVIII]
OZONOLYSIS
When ozone is passed through a solution of dihydrocodeine in formic
acid, a-ozodihydrocodeine [LII, R = Me] is formed. This, on hydrolysis,
affords dihydromorphinic acid [LIII], which is also obtained b y the
hydrolysis of a-ozodihydroethylmorphine [LII, R E t ] , the product of
ozonolysis of dihydroethylmorphine, showing t h a t ozonolysis involves
cleavage of the aromatic nucleus between carbon atoms 3 and 4 [371].
Electrolytic reduction of a-ozodihydrocodeine yields an acid (hydro-
lysis by the sulphuric acid used as solvent), originally called 5-desoxy-
dihydromorphinic acid [LIV], whilst catalytic reduction gives the
corresponding methyl ester [371]. The course of reduction has recently
been reinterpreted, and it is now known t h a t catalytic hydrogenation
involves saturation of a double bond giving methyl tetrahydromorphil-
actonate [LV, R = Me], whilst hydrolysis and hydrogenation affords
tetrahydromorphilactonic acid [LV, R = H] which can be esterified
with the introduction of only one methyl group to [LV, R = Me]. The
position of tlio double bond in [LV] is assumed [240]. Catalytic reduction
of dihydromorpliiiiio aoid [LULJ had earlier boon shown to involve the
CODEINE 71
ROOC
NMe
HO
[LII] [LIII] [LIV] [LV]
HO-CH2
MeOOC
HO-CH, HOOC
NMe ^fMe
MISCELLANEOUS REACTIONS
(a) Codeine is unaffected by Grignard reagents [374], but codeine
methyl ether forms simple addition complexes with ethyl- and phenyl-
magnesium halides; these are readily decomposed with liberation of the
unchanged base [375].
(b) Codeine condenses with benzaldehyde in the presence of sodium
othoxide to give a product of unknown constitution [376].
(c) Treatment of codeine with formaldehyde and concentrated
hydrochloric acid affords an ill-defined varnish-like substance of un-
known nature t o which the name dicodeylmethane has been given
[377]. Codeine has also been reported to react with hydrogen sulphide
in the presence of oxygen, b u t the nature of the product has not been
determined [378].
(d) With ^-nitrosodimethylaniline in alcohol codeine condenses to
give an intensely coloured substance, codeine violet. This compound,
which is soluble in alcohols to give dichroic solutions, will dye silks
and wool directly, but the dye is not fast to light. The platinichloride
has the composition Me 2 N-C 6 H 4 -N-G 7 H 1 8 Me-NO 4 -H 2 PtCl 6 , but the
constitution is unknown [379].
(e) Codeine reacts with ethyl chloroformate in chloroform in the
presence of potassium hydroxide to give a carbethoxy-derivative
isolated as bitartrate. I n general ethyl chloroformate appears to react
with tertiary amines in the same way as does cyanogen bromide, but its
sphere of activity is more limited [380].
(/) Codeine will form an addition compound with carbon suboxide,
in the proportions 1:5, which is stable to oxygen and water [381],
with phenolphthalein [382], and withp-acetamidophenol [383]. Codeine
forms double salts with narcotine [384-5], and salts with numerous
barbituric acid derivatives [386-92], of therapeutic interest.
(g) Sodium and potassium derivatives of codeine are reported to
result from boiling the alkaloid and the metals in benzene [393].
Thermochemical studies have been made b y Leroy [394-5]. The
absorption spectrum of codeine in the visible [396-7] and in the ultra-
violet [398-9] has been determined. The ultra-violet absorption curve,
compared with those of morphine and thebaine is given in K g . 1.
That of ethylmorphine is closely similar [400].
A L K Y L AND O T H E R S U B S T I T U T E D C O D E I N E D E R I V A T I V E S
(a) Treatment of codeinone [XXVII] with methyllithium affords 6-
mothyloodeme [LX], which can be degraded to a,- and /3-methine bases
and to 3-mothoxy-6-methyl-4:5-phenanthrylene oxide. Tt gives only
a poor yield of a 6-mothylohlorooodido with phosphorus pontachJorido,
CODEINE 73
4-5
CODEINE
MORPHINE
THEBAINE
4O
3-5
5
U)
30
25
2000 25OO 30OO 35OO
WAVELENGTH A
Fio. 1.
n
CH,OH OH2OH
[LXIII] [LXIV] [LXV] [LXVI]
ISOCODEINE
Isocodeine is one of the products of hydrolysis of a-chlorocodide
[244-5], -chlorocodide [238, 243, 250], bromocodide [244, 252], and
iodocodide [247]. (The name was applied to the product of mineral acid
hydrolysis of dihydrothebaine-< by Ereund [405], b u t this was a mis-
nomer, see Chap. XIV.) I t is also obtained by the methylation of
a-isomorphine [245, 252]. There was some initial confusion regarding
the identity of isocodeine [245, 252, 406-7], which forms a molecular
compound [m.p. 145-146 C ] with allo-^-codeine [244-5, 253], but this
was clarified by Lees [245].
That isocodeine differs from codeine only in the spatial arrangement
of the CH OH group was shown by the oxidation of both bases to
the same ketone, codeinone [xxvn] [305].
Although isocodeine is formed by the hydrolysis of both a- and /}-
chlorocodide, only the latter can be obtained from the reaction of iso-
codoine with thionyl chloride [238].
Catalytio roduction of isocodeine affords dihydroisocodeine [408],
which is convoniontly prepared directly from tho mixture of products
resulting from tho liydrolyHis of bromooodido [246]; it also results from
OH. IV ISOCODEINE 75
!/.-CODEINE
PREPARATION
i/(-Codeine is obtained by the hydrolysis of a-chlorocodide [249-50].
/3-chlorocodide [238, 250], and iodocodide [247], but it has apparently
not been isolated from the products of hydrolysis of bromocodide (see
Chap. VIII). I t is also obtained when codeine is heated with oxalic
acid during the preparation of apocodeine [256, 412] and is identical
with the ' amorphous codeine' resulting from the action of moderately
concentrated sulphuric acid on codeine [167-8, 172, 413-14]. Methyla-
tion of y-isomorphmo also gives ^-codeino [245, 407, 4] 5].
76 C O D E I N E AND I T S ISOMERS OH. IV
STRUCTURE
The relationship of j/r-codeine to codeine was demonstrated by the
oxidation of the former to s/f-codeinone [LXVII] [305, 416] and the
degradation of this to 3:4:8-trimethoxyphenanthrene [LXVIII] [305,
406, 416-17], indicating t h a t the hydroxyl group, at C-6 in codeine
[LXIX, R = OH], has moved to C-8 in (//-codeine [LXX].
REDUCTION
The reduction of ^-codeine is complicated by the presence in the same
molecule of an allylie ether and an allylic alcohol. Catalytic reduction
generally proceeds with opening of the cyclic ether system and produc-
tion of phenolic bases, but this can be suppressed by hydrogenating the
hydrochloride over platinum oxide.
(a) Reduction of tA-codeine hydrochloride in glacial acetic acid over a
platinum oxide catalyst gives 80 per cent, of the non-phenolic dihydro-
i/r-codeine-A [LXXI] [421]. This can be demethylated with hydriodic
acid to dihydro-y-isomorphine [421-2].
(b) Hydrogenation of the base in dilute acetic acid using a colloidal
palladium catalyst gives the phenolic dihydro-i/r-codeine-B [LXXII] to-
gether with a small amount of an isomer [421].
(c) Electrolytic reduction gives dihydro-</(-codeme-B [295, 423].
(d) Sodium and alcohol reduction of (//-codeine follows a different
course giving dihydro-i//-codeine-C [LXXIII] and the constant proportion
mixture of dihydrodesoxycodeines B [LXXIV] and C [LXXV] known as
dihydrodesoxycodeino-A (see Chap. IX) [423].
(e) Complete catalytic reduction of (//-codeine in dilute acid and of
dihydro-i//-oodeinos B and C gives tetrahydro-i/r-oodoino [LXXVI] [295,
408, 421, 423].
OH. IV ^-CODEINE 77
R E P L A C E M E N T OF HYDKOXYL
When i/i-Codeine is treated with phosphorus pentachloride or thionyl
chloride allylic rearrangement occurs and a-chlorocodide is formed
[238, 428]. jS-Chlorocodide results when i/r-codeine is heated under
pressure with concentrated hydrochloric acid, b u t this doubtless arises
by rearrangement of the a-isomer first formed [243]. Bromocodide is
produced by the interaction of i/r-codeine and phosphorus tribromide
[428]. With phosphorus pentachloride dihydro-i/<-codeine-A gives 8-
chlorodihydrocodide, with thionyl chloride chlorination only occurs in
the aromatic nucleus, and with phosphorus tribromide a poor yield of
8-bromodihydrocodide is obtained [240]. Tetrahydro-i/r~codeine gives
tetrahydro-^-chlorocodide with phosphorus pentachloride [295].
HOMANN DEGRADATION
Alkaline degradation of i/r-codeine methiodide affords e-codeimethine
[LXXXIII], which resists isomerization [415, 428-9], and this on further
degradation gives morphenol and acetylmethylmorphenol [428] (see
Chap. VIII). Methine bases have also been prepared from ^-codeine
methyl ether [411, 419], dihydro-i/r-codeine-A [421] and its methyl
ether [426], dihydro-^-codeine-B [421, 423], dihydro-i/r-codeine-C [295,
423] and its methyl ether [426], tetrahydro-^r-codeine [295] and its
methyl ether [426].
ALLO-i/r-CODEINE
Allo-i/r-codeine is the third product of hydrolysis of a-chlorocodide
[244-5, 250], jS-chlorocodide [238, 243, 250], bromocodide [243-4, 251,
253, 407], and iodocodide [247]. I t differs from i/r-codeine only in the
spatial arrangement of the CH-OH group, as is shown by the
production of i/f-codeinone when it is oxidized [305, 407, 416]. I t is
related to /3-isomorphine, from which it can be prepared by methylation
1245, 253]. Though it is formed by the hydrolysis of a-chlorocodide it
yields /3-chlorocodide exclusively when treated with phosphorus penta-
(ihloride [238, 305].
REDUCTION
The reduction of allo-i/<-codeine in general follows the same pattern
(is the reduction of ^-codeine, though elimination of the 8-hydroxyl
Jj[I1OUp is more facile, and occurs even during catalytic hydrogenation.
(a) Hydrogenation of the hydrochloride in glacial acetic acid over
platinum oxide affords 80 per cent. dihydroallo-i/r-codeine-A (epimer
of LXXI) together with small amounts of tetrahydroallo-^r-codeine
(opimer of LXXVI) and tetrahydrodesoxycodeine [LXXXV] [431].
(/;) Hydrogenation of the base in alcohol with palladized calcium
(wii'bonate gives equal amounts of dihydroallo-!/<-codeine-A and tetra-
liydroallo-i/i-codeine [431].
(c) Hydrogenation of the base in dilute acetic acid with colloidal
palladium as catalyst yields exclusively tetrahydroallo-^-codeine [295,
'CiI |.
{(I) Sodium and alcohol reduction yields the constant-proportion
mixture of dihydrodosoxycodeines B [LXXIV] and C [LXXV] and di-
liydroallo-i/i-oodomo-C (tho opimor of LXXIII) [431].
80 C O D E I N E AND ITS ISOMERS
Tetrahydroallo-i/t-codeine and dihydroallo-^-codeine-A can be pre-
pared by the demethylation of the corresponding derivatives of /?-
isomorphine [409].
Dihydro-^r-codeinone is obtained in 40 per cent, yield by the
Oppenauer oxidation of dihydroallo-i/r-codeine-A [304]. The latter on
treatment with phosphorus pentachloride gives 8-chloro- and 1:8-
dichlorodihydrocodide, which are also produced in the same way from
dihydro-i/f-codeine-A; thionyl chloride effects chlorination in the aroma-
tic nucleus only. With phosphorus tribromide it apparently suffers re-
placement of the hydroxyl group by bromine, loss of hydrogen bromide,
and demethylation, as the product is desoxymorphine-D [240] (see
Chap. VIII).
Degradation of the quaternary salts of allo-i/f-codeine affords -
codeimethine (the epimer of LXXXIII) [407] which cannot be isomerized
[428], and methine bases have also been prepared from dihydroallo-i/r-
codeine-A [431] and tetrahydroallo-^-codeine [295, 431*].
l-Aceto-8-acetylallo-i/r-codeine results from the action of acetic
anhydride and concentrated sulphuric acid on allo-i/f-codeine [430].
Two sulphonic acids result from the sulphonation of allo-i/f-codeine-
N-oxide, and these on bromination and reduction of the perbromide are
converted to 'bromoallo-^-codeine dibromide' [295].
Solvent
for Crystal Specific
Compound, m.p. C. recrystn. form rotation Temp. Solvent Refs.
Codeine . . . . . 156-157 Benzene prisms -111-5 15 CHCl8 59
-137-75 15 80%
EtOH
hydrochloride 2H2O . 287 H8O prisma -108-2 22-5 59
4S2-3
hydrochloride (anhyd.) 264 434
hydrobromide 2H 2 O . H8O + needles -96-6 22 H2O 434
BtOH
hydrobromide (anhyd.) 190-192 435-6
hydriodide-2H 8 0 266 H8O 167-8,
172
perchlorate . . . . explodes needles 437
sulphate 5H3O . . . . needles -101-2 H2O 59,167,
172,123
thiosulphate 5H8O H2O prisms 438
nitrate . . . . . H2O prisms 167-8
phosphate -2HjO needles 167-8
chromate 5H2O H2O needles 172
thiocyanate . . . . 100 H2O needles 167-8
platinichloride-4H 2 0 . needles or 167-8
granules
aurichloridc . . . . amorph. 172
mercurichloride-H 8 0 . needles 172
mcrcurliodide . . . . cryst. 439-41
stibnichlorido . . . . red-brown 442
plates
emporlodido (trl-lodldo) EtOH violet 331-2
crystals
pontiv-lodldo . . . . noodloB 333
lotrnohloro-lodldo HOAc orango 443
nocHlloH
liydmwin Io'2IT1O T), 100 nnndlos 444
liyilmFnrniKyiiiihln orynl, 104
liyilroiVri'loyaiililo oryit. 104
CODEINE AND I T S ISOMERS 81
Solvent
for Crystal Specific
Compound i.p. 0 O. recrystn. form rotation Temp. Solvent
Codeine iodozineate 445
fluorocolumbate. -94 446
'Keineckate' 447
acetate 2H a 0 D. 100 172
monochloracetate 163-154 452
dichloracetate . 156 452
trichloraeetate . 93 448
benzoate . 79 449
o-chlorobenzoate 134 449
m-chlorobenzoate 96 449
^-chlorobenzoate 162 449
o-bromobenzoate 139 449
m-bromobenzoate 99 449
2>-bromobenzoate 166 449
o-hydroxybenzoate 121 449-50
m-hydroxybenzoate 148 449
jj-hydroxybenzoate 162 449
o-nitrobenzoate . 185 449
m-nitrobenzoate 173 449
y-nitrobenzoate 189 449
camphorsulphonate 256 62-7 H, 451
dibromopyruvate 70 452
oxalate '3HjO . 167-8,
434
picrate 196-197 50% 453
BtOH
shikimate . 173-174 454
styphnate 115 455
trichlorobutyrate 173 452
tris-(2>-hydroxyphenyl)-arsenate D.245-246 456
o-guaiacolsulphonate . 164-165 HaO cubes 457-8
jj-toluenethiosulphonate EtOH leaflets 459
a-naphthalenethiosulphonate EtOH 459
18-naphthalenethiosulphonate EtOH 459
diethylbarbiturate c. 85 386
dipropylbarbiturate . 59'5 391
diallylbarbiturate 105 387, 389
phenylethylbarbiturate 80 388
p-acetamidophenate c. 125 HjO 383
methochloride-H a O . HjO 187
< methobromide . 261 Acetone prisms 175-7
+ Ha0
methiodide 2HjO HjO needles 187
27 H1O 461
metbiodide D. 270 EtOH -81 '9 17 99% 460
EtOH
methomethylsulphate 4HjO H1O rhombs. -180'1 15 HjO 187
methomethylsulphite . 177
methohydroxide notcryst.
- methoplatinichloride 3H a 0 orange 187
cryst.
cthobromide 5H a 0 176
-othiodide . Ha0 crystals 171
bonzyliodide 264
- Iodomethoehloride 235-238 needles 174
Iodomethiodide . 214-216 needles 174
Dlciidoine ethylene dichloride'4H 8 O 182-192 H1O needles 173
I (lcodoine ethylene dibromide 4H a 0 177-179 rhombs. 97'1 173
- platinichloride 172-3
- anrichloride . 172-3
(lodolno-narcotine hydrochloride D. 200 prisms 384-5
H'nmiylcodeine 180 EtOH needles 229-31
liydroohlorlde . needles 229-31
Aootylcodoine 133-5 EtjO prisms 237,187,
226
hydrochloride-2H a O . cryst. 187, 226
niollioohlorldo . cryst. 187
muMilodldo 250-252d, H1O needles 326
ntliloilldO'lH.O cryst. 187
n-KiinliicolHiilphonnlo . 11,0 prisms 457
I'rniilmiyktniliiliio . uot cryst, 187
- Iiyilruuhlorldo-S]TiO . 11,0 noodloB 187
M4T.1 a
82 CODEINE AND ITS ISOMEBS OH. IV
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Propionylcodeine hydriodide-H 2 0 . H1O needles 187
platinichloride . . . . yellow 187
cryst.
oxalate .3H 2 O . . . . cryst. 187
Butyrylcodeine . . . . not cryst. 224, 228
hydrochloride 3HjO . cryst. 224, 228
ethiodide-H 2 0 cryst. 224, 228
Succinylcodeine 5H2O . 80% 223
EtOH
hydrochloride -H 2 O . 223
Benzoylcodeine . . . . Et 2 O 228
hydrochloride -H8O . 228
methiodide . . . . 254 needles 462
ethiodide JH 2 O 85% 224
EtOH
Tartrylcodeine . . . . amorph. 223
Camphorylcodeine 4H2O EtOH 223
hydrochloride 3H2O . cryst. 223
p-toluenesulphonylcodeine 121-121-5 butanone -209-0 dioxane 283-4
126-128
picrate . . . . . 153-155 283
hydrochloride H2O . 154-156 283
Codeine 9-hydroxyfluorene-9-carb-
oxylate (ester) . . . . D. 258 233
Codeine phenylurethane . 141 prisms 462
methiodide . . . . 255-260 EtOH needles 462
Carbethoxycodeine. 77-78 -202-8 EtOH 380
bltartrate . . . . . 120 EtOH needles 380
bitartrate (hydrated) . 137-140 -120-3 H2O 380
Codeine methyl ether 140-141 MeOH prisms -194 22 EtOH 263
methochloride . . . . 208 EtOH prisms 263, 294
methiodide . . . . 257 80% prisms -109-7 15 H2O 262, 294
EtOH
methoplatinichloride . D. 215 needles 263
methopicrate . . . . 211-212 H2O needles 263
benzyl iodide . . . . 181 264
N-oxide hydriodide 253 263
Dihydrocodeine H2O 62-63 H2O octa- 267-8,
hedra 296
/() 55 -118-0 96% 269
Dihydrocodeine 2H2O (2 forms) (,., EtOH
82-87 H2O 313, 241,
269
Dihydrocodeine (anhydrous) . 112-113 269, 271,
296
hydrochloride . . . . 256 296
acid tartrate-H 2 O 192d. -66-0 25 H2O 463
diethylbarbiturate 390
diallylbarbiturate 95 H2O 386-7
methiodide . . . . 257 EtOH 241
chromate . . . . . 299
Kacemate with antipode from sino-
menine series . . . . 105 prisms 0 275
methiodide . . . . 257 MeOH 0 275
( + ) dihydrocodeine 2H 2 O 87-88 275
( + ) dihydrocodeine (anhydrous) 110 + 146-4 30 EtOH 275
methiodide . . . . 257 EtOH + 80-1 30 H2O 275
Aeetyldihydrocodeine 120 Et 2 O + 353-4
petrol
Dihydrocodeine methyl ether . 83 Et 2 O or -153-4 18 EtOH 263,
petrol 276-8
hydrochloride 3H2O . 115-116 H2O + needles 276
acetone
picrate . . . . . 222 EtOH+ needles 282
toluene
mothiodide . . . . 135-140 H2O 276
and 212
1-olilorocodolnci-1111,0 . 175-17 EtOH noodles -147-2 10 EtOII 327,
107-8
hy-lronhlorliln . noiidldH 327
- - ul[>liaU\"Hl,(> prlHiiiH 827
plaMnlolilorlUn . . . . .. MnOCJ)Jl, I ,. .. 327
OH. IV CODEINE AND ITS ISOMERS 83
Solvent
for Crystal Specific
Compound up. C. recrystn. form rotation Temp.
1-chlorodihydrocodeine . 196 BtOH octa-
hedra
1-bromocodcine-J or -IH11O 161-162 H2O + prisms
BtOH
hydrochloride . needles
hydrobromide 'HjO . H1O prisms
platinichloride . yellow
amorph.
picrate D. 235 H1O +
BtOH
methochloride 2JH 1 O H2O needles
methiodide H2O 242-244 H1O prisms
ethiodide .
N-oxido-H 2 0 . 200-201d, H1O
N-oxide hydrobromide D. 242 EtOH + rods
Bt 1 O
1-bromodihydrocodeine . 190 BtOH octa-
hcdra
'Bromocodeine dibromide' 200
2-bromocodelne 160-161 needles
Tribromocodetne . amorph.
Diiodocodcine yellow
cryst.
1-nitrocodeine 221-222 EtOH
hydrochloride . amorph.
sulphate . needles
platinichloride -4HjO
oxalate prisms
methiodide
6-acetyl-l -nitrocodeine 203 leaflets
tx-nitrocodeine 197 EtOH plates
2-nitrocodeine H3O 116-117 prisms
hydrochloride . D. 249
1-aminocodeine 226 EtOH plates
hydrochloride . D. c. 290
Diacetylaminocodeine 120 MeOH needles
methiodide 251-252
2-aminocodeine 95-96-5 prisms
perchlorate D. 170
1 -nitrodihydrocodoine 221 BtOH double
pyramids
n-nitrodihydrocodeine 180 EtOH needles
I -hydroxycodeine -H 2 O 176 BtOH needles
284
-hydrochloride-2H 2 O cryst.
I -acetocodeine -H3O 150 21
oxime D. c. 100 amorph.
methiodide D. c. 235 H2O needles -64 15
O-acctyl-l-acetocodeine JH 2 O 125-126 EtOH -208 20
2 forms 146-147 EtOH -207 20
oxime I E t O H . 176-178 EtOH
O-acotyl-1-acetodihydrocodeine 166-167 BtOAc -105 20
l-Mcotodihydrocodeine . 138-140 BtOAc -101 20
I -(I '-hydroxyethyl)-codeine 222-224 H1O -101 20
0-ncotyl-l-(l'-hydroxyethyl)-codeine 185-187 60% -212 20
EtOH
acid tartrate-H 2 O 165-170 H1O -115 20
I ( I '-bydroxyethyl)-dihydrocodeine . 225-227 60% rods -82 20
EtOH
<l-n(yl-l-(l'-hydroxyethyl)-
iLlliydrooodelno . 251-252 EtOH -91-2
(!-acetyl- 1-othyldihydrocodorne 104-105 -126
iiolil-l iirlrotB' H 1 O 160-170 H2O
Il (or l())-liy(li'oxycodoino 207-208 Benzene
or HOAc
liydriialilurldo . 11,0 cryst.
picmlo 100 IJ1O
- l/laioliiu&U) . J 70 IDtOJt
84 C O D E I N E AND I T S ISOMEKS OH. IV
Solvent
for Crystal Specific
Compound m.p. 0. reerystn. form rotation Temp. Solvent Refs.
9 (or 10)-hydroxycodeine methiodide
-MeOH 240-250 MeOH 307
9 (or 10)-hydroxycodeine methine, i.e. 50-60 Bt 2 O 307-9
9 (or 10)-ketodihydrocodeimethine
hydrochloride . . . . D. c. 246 307
hydriodide . . . . 220 307
picrate . . . . . 211 307
picrolonate . . . . D. 140 307
methiodide-IiH 2 O 220 307
oxime hydrochloride . 279 310
oxime methiodide 270 310
- - semicarbazone . . . . 106-107 309
Acetyl-9 (or 10)-ketodihydrocodei-
methine . . . . . 81 310
hydrobromide . . . . 280-285 310
hydriodide . . . . 270 310
methiodide . . . . D. 260 310
Diacctylhydroxycodeine . 160-161 BtOH 297, 310
hydriodide . . . . 230 297, 310
methiodide . . . . 248-255 310
1 -nitro-9 (or 10)-hydroxycodeine D. 232 MeOH 340
7-hydroxydihydrocodeine 225 317
Dibenzoyl-7-hydroxydihydrocodeine. 2 317
7:8-dihydroxydihydrocodeine . 208-209 BtOH plates 316
Triacetyl-7:8-dihydroxydihydro-
codeine . . . . . 200 MeOH plates 316
perchlorate . . . . 281 H2O needles 316
14-hydroxycodeine and derivatives: se s Chap. XT
Codeine-N-oxide . . . . 230-231 an.H2O tablets 348
hydrochloride . . . . cryst. 348
hydrobromide . . . . 196 348
nitrate . . . . . 187 348
acetate cryst. 348
Codeine-N-oxide (dimoleeular) 7H2O 200-202 C 97-6 20 H 2 O-) 349
1-107-2 19 EtOH/
N-oxide (monomolecular) from the
dimoleeular oxide 215 -97-1 18 H2O 349
hydrochloride H 2 O 219-220 -105-8 20 H2O 349
a-codeine-N-oxide sulphonic acid 339, 350
/3-codeine-N-oxide sulphonic acid 272 -115-4 20 2N- 339, 350
KOH
Mtro-a-codeine-N-oxide sulphonic aeid D.167-170 339, 350
Codeine sulphonic acid . D. > 300 needles -136-3 20 2N- 339, 350
or prisms KOH
methohydroxide D. 284 H2O needles -63-2 20 H2O 339, 350
465
0-codoine sulphonic acid D. c. 243 plates -190-1 20 v. dil. 339
KOH
y-codcine sulphonic acid D. c. 280 50% plates 339
EtOH
1 )ihydrocodeine-N-oxide D. 225 rhombs. 341
hydrochloride . . . . 217 341
picrate . . . . . 161-162 341
Dihydrocodeine-N-oxide sulphonic
acid 273-275 prisms 341
a-dihydrocodeine sulphonic acid 315-320d cryst. -88 20 H2O 341
powder
P-dihydroeodeine sulphonic acid D.330-340 H2O + prisms -76-7 20 v. dil. 341
EtOH and alkali
leaflets
methohydroxide D.280-285 H2O + plates 341
BtOH
'Norcodolno 185 BtOAc or plates or 352-3,
acetone needles 357, 360
hydrochloride 811,0 . 309 354
liydrlodldo.2ir,0 257 354
pMlulohlorltlo . . . . 289 354
ploroto non- 354
oryst.
tlrtnonrlmnlHiln . . . . 210 MtOH 354
JHiuKtliylnotmdoltia 17(1- L78 BtOH 357
AoatyloyariQUorooitelno 181 MtOII .. ,, ,, !153-5
OH. iv CODEINE AND ITS ISOMERS 85
Solvent
for Crystal Specific
Compound m.p. 0. recrystn. form rotation Temp. Solvent Refs.
Cyanonorcodeine . . . . 262 powder 353-5
JT-ethylnorcodeinc . . . . 203 361
N-propyluorcodeine oil 361
hydrochloride . . . . 185 361
platinichloride 216 361
N-m-butylnorcodcine 100 361
platinichloride . . . . 205 361
N-jsoamylnorcodeine oil 361
platinichloride 3H a 0 . 207 361
picrato . . . . . 100 361
N-(|3-hydroxyethyl)-norcodemo 197 needles 361-2
N-benzylnorcodoine < 60 361
H-phenylethylnorcodeine 114 354
hydrochloride . . . . 277 Bcalea 354
platinichloride . . . . 216-217 354
N-(y-hydroxypropyl)-norcodeine 133 366
picrate . . . . . 120-121 plates 366
N-(y-benzoyloxypropyl)-norcodeine . 47 366
picrate . . . . . 118-119 366
methiodide . . . . 169-170 366
N-allylnorcodeine . . . . 95 361
hydrochloride . . . . 125 361
platinichloride . . . . 214 361
allyliodide. . . . . D. 208 361
N-(y-chloroallyl)-norcodeine 54-56 367
hydrochloride . . . . 120 367
picrate . . . . . 124 367
methiodide . . . . 115 367
N-(y-bromoallyl)-norcodeine . 68-70 367
picrate . . . . . 127 367
N-dibromoallyln orcodeino c. 60 367
N-/3-butenyInorcodeine . 44 363
hydrochloride . . . . 128 363
-platinichloride . . . . 198-208 363
N-cyclopropylmethylnorcodeme amorph. 364
--hydrochloride . . . . 250-252 364
-platinichloride . . . . 1X199-200 364
N -cyclobutylmethylnorcodeine not cryst. 364
-hydrochloride . . . . 150 364
-platinichloride . . . . D. 217 364
N"-eyclopentyrmethylnorcodeine 50 364
- picrate . . . . . 125-128 364
- hydrochloride . . . . 171-174 364
N-cyclohexylmethylnorcodeine 55-60 364
- hydrochloride . . . . 171-176 364
picrate . . . . . 132-135 364
N-cycloheptylmethylnorcodeine 59-61 364
- picrate . . . . . 139 364
N-(p-cycIopropylethyl-)norcodeine . notcryst. 364
hydrochloride . . . . D. 160 364
N -<-thienykiorcodeine 76 364
hydrochloride . . . . D. 200 364
picrate . . . . . C 145 364
N -eyclopentenylnorcodeine 365
hydrochloride . . . . 188 365
N-rlmmmylnorcodeine . 78 369
platinichloride . . . . D. 208 369
N-pmpargylnorcodeine . 95 364
(anhydrous) . . . . 137 364
innlhiodide . . . . D. 172 364
N-p-ultrophcnylnorcodeine 212 366
N-a: <l-rthiitrophenylnorcodeine 265 366
N -2; <l -dlaminophenylnorcodeine 233 366
Trla<iotyl-N-2:4-diaminophenylnor-
nnddlno . . . . . 144-146 366
I ayitnoRcn bromide . 148-149 366
NMirapn rKyl-1-bromonorcodeine ? 100-102 364
I :<l-dlnorcodoyl-/3-butono 132 369
N-nll ronoiioreodolno 246 BtOII pyramids 354, 360
+ 11,0 or platos
Niiriiiulylliydriusliio. 174 TdW)U 1-130 20 cmci, 350
liydmolllorhlu-iSJIiO . I l!B .. .. .. . 850
86 C O D E I N E AND I T S ISOMERS
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Norcodylhydrazine hydrochloride
(anhyd.) 182-185 + 116 20 EtOH 356
Tetrazone . . . . . 232 356
1-aminonoreodeine... . 221 BtOH 356
hydrochloride . . . . D. 235 356
platinichloride . . . . leaflets 356
Triacetyl-l-aminonorcodeine . 160-162 356
1-aminocyanonorcodeine. 288 needles 356
hydrochloride . . . . > 300 356
platinichloride . . . . cryst. 356
1-nitronorcodeine . . . . 185 yellow 353, 356
cryst,
hydrochloride . . . . cryst. 356
Diacetyl-1-nitronorcodeine 251 356
1 -nitro-N-tsoamylnorcodcine . 90 361
Acetyl-l-nitro-N-isoamylnorcodelne . 62 361
1-nitro-N-nitrosonorcodeine 236 356
Norcodeine sulphonic acid D. 335 352, 339
Bihydronorcodeine. 194 EtOH 353-4,
356
hydrochloride . . . . 295 356
platinichloride . . . . D. 245 red 356
needles
Cyanodihydronorcodeine. 213-214 354
Acetylcyanodihydronorcodeine 227-228 EtOH needles 354
N-allyldihydronorcodeine oil 361
allyliodide 157 361
Hofmann degradation product from
N-allyldihydronorcodeine allyl
iodide . . . . . oil 361
platinichloride . . . . 78 361
allyliodide. . . . . 173 361
N-nitrosodihydronorcodeine 198 H1O 356, 360
Nordihydrocodeinium-piperidinium
iodide . . . . . 271 370
Nitrocodeinic acid . . . . Dec. needles 340
hydrochloride . . . . da. itci yellow 340
needles
barium, salt -2H2O 340
potassium salt . . . . 340
methyl ester-2MeOH . McOH plates 0 340
methyl ester hydrochloride . needles 340
ethyl ester hydrochloride . 340
hdiazomethane^C19HJjO8N2 180 340
Nornitrocodeinic acid needles 340
Aminocodeinic acid hydrochloride . 340
Noraminocodeinic acid . 340
o-ozodihydrocodeine oil 371
hydrochloride . . . . f 242 + 77-6 16 H2O 371
1235-236 + 78-8 20 H2O 246
hydriodide . . . . D.248-250 H2O 371
hydrohromide . . . . D. 238 rhombs. 371
picrate . . . . . D.238-239 371
methiodide . . . . D. 155 371
Acetyl-a-ozodihydrocodeine oil 371
picrate . . . . . D.208-209 371
/3-ozodihydrocodeine oil 372
hydriodide . . . . D. 229 HjO plates + 52-4 20 H2O 372
and
needles
Dlhromo-P-ozodihydrocodeine D. c. 222 96% leaflets 372
EtOH
y-ozodihydrocodoine oil 372
hydrlodido . . . . 219-220 rods 372
oi-ozodlhydroothylmorphine oil 371
hydrlodido . . . . D.255-256 EtOH needles + 69-1 17 H2O 371
/3-ozodIIiydroothylmorphino . 170-5 11,0 H- prisms + 24-4 18 EtOH 372
EtOH
yossoUlliyrtronMiylmorplilno J 7 5 H1O-I- noodles -8-2 18 EtOH 372
HtOH
O-aliloru-rt-oxoUlliydruondnlno . . I57-JB8 0(1% noodlui 871
MtOJI "
C O D E I N E AND I T S ISOMERS 87
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temv- Solvent Eefs.
6-chloro-a-ozodihydr-ocodeine picrate D.249-250 371
Dihydromorphinie acid . 227 EtOH needles + 30-9 16 H2O 371
Tetrahydromorphinic acid 217-218 BtOH 371
Tetrahydromorphilactonic acid 245-246 BtOH + 29-0 22 EtOH 371, 246
amide . . . . . 226-228 -3-4 19 BtOH 246
Methyl tetrahydromorphilactonate . 147-148 BtOAc + 6-3 19 EtOH 371, 246
picrate . . . . . 228-229 371, 246
hydrochloride . . . . 247-248 plates + 13 18 H2O 371
hydriodide . . . . D. 195 plates 371
mcthiodide . . . . 183-184 371
N-oxide . . . . . D. 183 EtOH + 19-7 30 H2O 372
N-oxide hydrochloride D.195-199 372
N-oxide picrate . . . . D. 196 372
Methyl acetyltetrahydromorphilac-
tonate . . . . . oil 371
methiodide . . . . D. 225 70% needles 371
EtOH
Methyl 6-chlorotetrahydromorphilac- 143 96% 371
tonate EtOH
picrate . . . . . 213-214 371
Ethyl tetrahydromorphilactonate oil 371
picrate . . . . . D.234-235 371
Tetrahydiomorphitetrol . oil 246
picrate . . . . . D.178-179 EtOH + 25 20 50% 246
acetone
methiodide . . . . 192-194 EtOH + 36-7 19 H2O 246
Tetra-acetyltctrahydromorphitetrol
methiodide . . . . 236-237 BtOH + 4-5 19 H2O 246
Dihydrocodinal phenylhydrazone D. 247 yellow 373
hydriodide rods
Dihydrocodinal semicarbazone D. 278 373
/3-dihydrodiconal . . . . 372
-oxime-2H20 . . . . D.268-287 372
oxime hydrochloride-H 2 O . D. 266 372
phenylhydrazone acetate-H 3 O 206-206 372
semicarbazone . . . . D. 247 372
Dicyanocodeine . . . . EtOH + 167-8
Bt 2 O
Oodeine-carbonsuboxide . 155-16Od. orange 381
powder
Dicodeylmethane . . . . varnish 377
hydrochloride . . . . D. 140 377
Hodium codeine . . . . yellow 393
powder
Potassium codeine . . . . cryst. 393
O-methylcodeine . . . . 114-5- ligroin -163 20 BtOH 401
116-5
- ~ perchlorate . . . . 139-144 BtOH 401
salicylate . . . . . 167-169 BtOAc prisms 401
- mcthiodide . . . . 232-233 MeOH 401
(l-iiiothyldihydrocodeine . 116 Subl. -139 20 BtOH 402
hydrochloride . . . . 268-273 Et2O+ -112 20 BtOH 402
BtOH
acid oxalate -JH 2 O 240-241 90% -99-5 20 EtOH 402
EtOH
mcthiodide . . . . 251-252 MeOH -86-3 20 BtOH 402
(l-ncotyI-6-methyldihydrocodeine 124-5- Subl. -85-1 20 BtOH 402
125-5
I -cliloro-6-niethyIdihydrocodeine oil 402
hydriodide . . . . 260-262 BtOH -73-6 20 EtOH 402
perchlorate . . . . 238-239 BtOH -81-4 20 EtOH 402
I -liromo-6-methyIdihydrocodeine amorph. 402
hydriodide . . . . 248-249 H2O -64-6 20 BtOH 402
methiodide . . . . 235-237 Et 2 O + -73-1 20 EtOH 402
MeOH
(I^tliyldlhydrocodoine oil 402
- jilorato 217-219 75% -73-0 20 EtOH 402
BtOH
. mothlodldo 288-240 Bt 1 O +
-82-0 20 EtOH 402
MoOn
A-M-nmylillliyilromdoJnn . oil -108 20 KtOH 402
(!jiliuiiyldlliyilraouiluliio oil -J65 20 MtOU 402
88 CODEINE AND ITS ISOMERS OH. IV
Solvent
for Crystal Specific
Compound m.p. 0 O. recrystn. form rotation Temp. Solvent Refs.
6-phenyldihydrocodeine hydro- 190-191 Et 2 O + -131 20 BtOH 402
chloride BtOH
perchlorate . . . . 246-248 -126 20 BtOH 402
acid oxalate EtOH . 126-127 Et 2 O + -117 20 BtOH 402
BtOH
Other alkyl-dihydrocodeines: see Chap. XIX.
7:7-bis-[hydroxymethyl]-dihydrocodeine: see Chap. X.
Isocodeine 171-172 BtOAc -150-6 CHCl,
acid tartrate 185-186 MeOH plates -99-4 H2O
binoxalate 235 EtOH
acid oleate
methiodide 270 MeOH leaflets -102 15 H2O
Isocodeine methyl ether . 80-82
salicylate . 158-159 BtOH -122-4 24 EtOH
methiodide 189-200 EtOH plates -111-6 22 H2O
Dihydroisocodeine . 199-200 EtOH prisms
acid tartrate 3 H , 0 c. 180 -62-4 26 H2O
acid tartrate 192 -65-3 29 H2O
picrate 235-237
methiodide 272
Acetyldihydroisocodeine. 166 H2O +
EtOH
methiodide 268-269
6-acetyl-l-acetoisocodeine iEtOH 80-85 EtOH +
H2O
6-acetyl-l-acetoisocodeme (anhyd.) 105 -236 14 CHCI2
Isocodeine-N-oxide D. 219 Et 2 O +
EtOH
n-Isocodeiae-N-oxide sulphonie acid D. 290 H2O prisms
/3-Isocodeine-N-oxide sulphonie acid D. c. 300 H2O leaflets
'Bromoisocodeine dibromide* . 212 H2O +
EtOH
Ozodihydroisocodeine oil
perchlorate . . . . 206-208 BtOH + 22-6 20 H2O
Tetrahydro-a-isomorphilactonic acid D.243-245 BtOH 00 18 H2O
Methyl tetrahydro-<*-isomorphi- non-cryst.
Iactonate . . . . .
picrate . . . . . 218d. BtOH + 2-4 22 H2O
Tetrahydro-<-isomorphitetrol . oil
picrate . 168-169 Benzene -4-5 22 H2O
+ EtOH
Tetra-acetyltetrahydro-a-iso-
morphitetrol methiodide 203d. EtOH -8-5 18
Solvent
for Crystal Specific
Compound m.p. C. reerystn. form rotation Temp. Solvent Refs.
Allo-^-codeine . . . . 116-117 BtOH needles -235-4 21 EtOH 245, 295
hydrochloride . . . . 256-257 prisms -199 25 H2O 463
hydriodide . . . . D.280-285 H2O -153 15 H2O 407
methiodide . . . . 215-216 EtOH -142 15 H2O 243, 245,
253, 407
Acetylallo-'/'-codeine 194-195 EtOH needles 407
methiodide . . . . 260 407
Dihydroallo-iA-codeine-A 78-79 BtOAc + -105 25 EtOH 431
petrol
hydriodide . . . . 255d. EtOH -70 26 H2O 431
perchlorate . . . . 265-270 H8O -83-0 30 H2O 431
acid tartrate 124-125 H2O -50 25 H2O 431, 463
and
160-163
Dihydroallo-i/i-codcine-C . oil 431
perchlorate . . . . 145-147 H2O -16 25 H2O 431
methiodide . . . . 247-248d. BtOH -55 27 H2O 431
Tetrahydroallo-if-codeine -EtOAc 113-118 BtOAc scales -52 25 EtOH 431
Tetrahydroallo-*-codeine (anhyd.) . 145-5 subl. -58 25 EtOH 295, 431
hydrochloride . . . . 245-248 + 1-8 24 H2O 467
perchlorate . . . . 102-104 H2O -35 23 H2O 431
methiodide . . . . / 252 H2O needles 295
1241-242 MeOH -22 27 H2O 431
Diacetyltetrahydroallo-i/'-codeine 115 295
Allo-*-codeine-N'-oxide \ f n m , 271 295
sulphonic acid / A IormB D. 280 295
'Bromoallo-0-codeine dibromide' 206-207 EtOH 295
8-acetyl-l-acetoallo-t/'-codeine . oil 430
BIBLIOGRAPHY TO CHAPTER IV
1. ROBIQTJET, Ann. Ohim. Phys., 1832 (2), 18. H O F F M A N N - L A R O C H E AND CO., Brit.
51, 225. Pat. 457,433 (27 Nov. 1936).
2. Ann., 1833, 5, 82. 19. French Pat. 804,543 (1-936).
3. ~DB,AaENDOw,DieHeilpflanzen(TZnck(}, 20. Swiss Pat. 186,666 (1936).
S t u t t g a r t , 1898). 21. D.R.-P. 640,859 (1937); Frdl. 2 3 ,
4. AKIMA a n d I W A K I B I , Rept. Inst. Sci. 449.
Res. Manchoukuo, 1938, 2, 221. 22. F B E Y and WtEST, U.S. Pat. 2,132,945
5. KEBBOSCH, Arch. Pharm., 1910, 2 4 8 , (11 Oct. 1939).
536. 23. KANEWSKAJA, J. pr. Ghem., 1924 (2),
6. CHOKRA a n d GHOSE, Indian J. Med. 108, 247.
Re-s., 1931, 19, 415. 24. B A B B I E B , Ann. pharm. Franc., 1947,
7. KLYACHKINA, RUSS. Pat. 53,168 (31 5, 1 2 1 ; Ghem. Abs., 1948, 4 2 , 1023.
May 1938). 25. H O M E Y E R and SHILLING, J. Org.
8. MEBLIS,ZAIONTS,andLABENSKII, Ghem., 1947, 12, 356.
Russ. Pat. 53,224 (31 May 1938). 26. L E V I and CASTBLLI, Gazz. Ghim. Ital.,
0. GBBOOBY, Ann., 1833, 7, 261. 1938, 68, 459.
10. MEECK, Ann., 1834, 11, 279. 27. Ara. UoI. (SSo Paulo), 1939,
11. ibid., 1836, 17, 79. 2 3 , 263.
12. M O H B , ibid., 1840, 3 5 , 119. 28. Anales farm. bioquim.
13. H E S S B , ibid., 1870, 153, 47. (Buenos Aires), 1940, 1 1 , 6 .
14. Ann. Suppl., 1872, 8, 261. 29. R B I M B B S and GOTTLIEB, DansJc Tids.
15. Pixtaam, Bee. Tram. Ohim., 1887, 8, Farm., 1943, 17, 54.
201. 30. MlLLMB, Ann., 1851, 77, 381.
15. Arch. Pharm., 1887, 225, 343. 31. DiCAN and B B A D Y , J.O.S., 1865, 34.
17. BiTHBU and ftumw, Khim. Farm,. 82. GAirmraiT, Oompl. Rmd., 1913, 156,
Prom., 1083, J 27. UOl.
OH. iv CODEINE AND ITS ISOMEBS 91
33. K B E M A N and SCHNIDEBSCHITZ, 67. RASMUSSEN a n d ScHOir, Z. Mektro-
Monatsh., 1914, 35, 1423. chem., 1925, 3 1 , 189.
34. KEFEBSTEIN, Pogg. Ann. der Physik, 68. K X E B B B , J.A.G.S., 1895, 17, 822.
1856 (4), 99, 275. 69. KIPPENBEBGER, Z. anal. Chem., 1900,
35. SENABMONT, Jahresber. Fortschr. 39, 201.
GUm., 1857, 416. 70. K O L T H O I T , Z. anorg. Chem., 1920,
36. ABZBTTM, Z. Krist., 1877, 1, 302. 112, 196.
37. H E Y D I C H , Z. Krist. Mineral., 1910,48, 71. MASSUCCI and MOFFAT, J. Am.
270. Pharm. Assoc, 1923, 12, 609.
38. W H E R B Y and YANOWSKY, J. Wash. 72. M U L L E E , Z. Elektrochem., 1924, 30,
Acad. Sd., 1919, 9, 505. 587.
39. SOHBODEE, Ber., 1888, 13, 1075. 73. H E S S E , Ber., 1871, 4 , 693.
40. K L E Y , Bee. Trav. CHm., 1903, 22, 367. 74. Arch. Pharm, 1878, 212, 330.
41. W E I G H T , J.A.G.S., 1916,38, 1647. 75. ibid., 1871, 198, 29.
42. RAKSHIT, Analyst, 1921, 46, 481. 76. COTJEEBE, Ann. Chim. Phys., 1836,17,
43. KTTBLY, Jahresber. Fortschr. Ghem., 166.
1866, 823. 77. MOKEANTZA, Bull. Soc. Chim. Boy.
44. EOUQUBT, Bull. Soc. GMm., 1897 (3), Yougoslav., 1932, 3 (3), 171.
17, 464. 78. EKKBBT, Pharm. Zentralhalle, 1930,
45. J. Pharm. Chim., 1897 (6), 5, 49. 71, 550.
46. SOHINDELMEISEE, Ghem. Ztg., 1901, 79. TATTEBSAiIi, Chem. News, 1879, 4 0 ,
25, 129. 126.
47. KNOLL, Arch. Pharm., 1887,225, 343. 80. ViTALi, Ber., 1881, 14, 1583.
48. TAMEAOH and HENICE, Pharm. Zentral- 81. LAFON, Compt. Rend., 1885,100, 1543.
halle, 1897, 38, 159. 82. DA SILVA, ibid., 1891, 112, 1266.
49. S M A H and LTJTZ, The Chemistry of The 83. E M A S , Pharm. Ztg., 1901, 46, 394.
Opium Alkaloids ("U.S. P u b . Health 84. LiNKE, Ber. Deut. pharm. Ces., 1901,
Suppl. 103, 1931). 11, 258.
50. K E A F T and W E I L A N D T , Ber., 1896, 29, 85. KOBBBT, Chem. Zent., 1899, ii. 149.
2240. 86. E K K E B T , Pharm. Zentralhalle, 1934,
51. KBMFV, J. pr. Chem., 1908 (2), 78, 75, 50.
201. 87. PESEZ, J. Pharm. Chim., 1937,25, 504.
52. E D B E , Schweiz. Wochschr., 1931, 5 1 , 88. K U L ' B E B G and PBESMAN, Farm. Zhur.,
228, 241, 253. 1940, 13 (3), 12.
53. H E I D U S C H K A and M E I S N E B , Arch. 89. EKKBBT, Pharm. Zentralhalle, 1926,
Pharm., 1923, 261,, 102. 67, 498.
54. BOTOLFSEN and PATTLSSEN, Bull. Soc. 90. R A B Y , J. Pharm., 1884 (5), 9, 402.
Chim., 1946, 390. 91. BEOOINEB, ibid., 1889 (5), 20, 390.
55. J A N O T and CHAIGBNBATT, Corrvpt. 92. E K K E B T , Pharm. Zentralhalle, 1928,
Bend., 1947,225, 1371. 69, 433.
56. BJOBLING, Acta Ghem. Scand., 1947, 1, 93. SOHNBIDEE, Pogg. Ann. der Physik,
392. 1872 (5), 27, 128.
57. WILLSTAEDT, Swed. Pat. 98,873 (14 94. J . pr. Ghem., 1873 (2), 6, 455.
May 1940). 95. VAN lTAiiLiE and STEENHAUEB, Pharm.
58. DREVON,Bull.Soc. CUm., 1940, 7, 732. Weekblad, 1927, 64, 925.
59. H E S S E , Ann., 1875, 176, 189. 96. Arch. Pharm., 1928, 265,
60. BOTTCHARDAT and BOTJDET, J. Pharm. 696.
Chim., 1853 (3), 2 3 , 292. 97. D A V I D , Pharm. Ztg., 1925, 70, 969.
01. Ann., 1853, 88, 213. 98. D E E B , Pharm. Monatsh., 1925, 6, 117.
(12. GRIMAUX, Compt. Bend., 1881, 92, 99. ViTALi, VOrosi, 14, 405.
1228. 100. J.G.S., 1892, 755.
(13. TYKOOINEE, Bee. Trav. Chim., 1882,1, 101. ABOY and VALDIGXTIE, J. Pharm.
144. Chim., 1926 (8), 4, 390.
(M. RAKSHIT, J. Phys. Ghem., 1930, 34, 102. and ALOY, Bull. Soc. Chim.,
2539. 1926 (4), 39, 729.
(15. LtoiioY, Arm. Ohim. Phys., 1900 (7), 103. H A A S , Pharm. Weekblad, 1930, 67,
21, 87. 508.
00. KAHMUHSKN unci SOITOIT, Pharm. 104. SMITH, Chem. News, 1879,40, 26.
ZmkalhalU, 102'), 65, 721). 105. Bar., 1870, 12, 1420.
92 CODEINE AND ITS ISOMERS CH. IV
244. L E E S and TTJTIN, Proc. Chem. Soc, 278. BOEHBINGEB-SOHN, D. B.-P. 503,924
1906, 22, 253. (1927); Frdl. 17, 2350.
243. J.C.S., 1907, 1408. 279. VONGEBICHTEN, Ber., 1899,32, 1047.
246. R A P O P O B T and P A Y N E , J. Org. Chem., 280. K N O B E , Ber., 1907,40, 3861, footnote
1950, 15, 1093. 2.
247. K N O E B and HAETMANN, Ber., 1912, 281. L U T Z a n d SMALL, J.A.C.S., 1934, 56,
4 5 , 1350. 1738.
248. SMALL and COHEN, J.A.G.S., 1931, 282. BENTLEY, Unpublished work.
52, 2214. 283. K A B E E B and WIDMABK, HeIv. Chim.
249. K N O B R and H O B L E I N , Ber., 1906, 39, Acta, 1951, 34, 34.
4409. 284. RAPOPOBT a n d BONNEB, J.A.C.S.,
250. ibid., 1908,41, 969. 1951, 7 3 , 2872.
251. SOHRYVEB a n d L E E S , J.C.8., 1900, 285. QRIMAXTX, Ann. Chim. Phys., 1882 (5),
1024. 27, 273.
252. ibid., 1901, 563. 286. PSOHOBB, R O T H , a n d TANNHATJSEB,
253. L E B S , Proc. Chem. Soc, 1907,23,200. Ber. 1906, 39, 19.
254. GTOLLAND and ROBINSON, J.C.S., 287. K N O B E a n d SMILES, ibid., 1902, 3 5 ,
1923, 980. 3010.
255. CHEM. F A B B I K . W I E E N I K , D. B.-P. 288. VONGEBICHTEN and SCHROTTER, ibid.,
489,185 (1925); Frdl. 16, 2485. 1882, 15, 1484.
256. K N O B E and R O T H , Ber. 1907,40,3355. 289. F I S C I I E B and VONGERICHTEN, ibid.,
257. andRAABE,ibid., 1908,41,3050. 1886, 19, 792.
258. PSOHOBB, J A E C K E L , and F E C H T , ibid., 290. K N O E B , ibid., 1899,22, 181.
1902, 3 5 , 4377. 291. VONGEBICHTEN, ibid., 1896, 2 9 , 65.
259. FOLKBBS, J.A.C.S., 1936, 58, 1814. 292. MOSETTIG a n d M E I T Z N E E , J.A.C.S.,
260. HAWTHOBNE, Dissert. (Jena), 1903. 1934, 56, 2738.
261. VONGEBICHTEN and MXJLLEB, Ber., 293. RAPOPOBT, J. Org. Chem., 1948, 1 3 ,
1903,36, 1590. 714.
262. PSCHOBR and DICKHATTSEB, ibid., 294. FALTIS andHECZKO, Monatsh., 1922,
1911, 44, 2633. 43, 255.
263. MANNIOH, Arch. Pharm., 1916, 254, 295. S P E Y E B and K B A U S S , Ann., 1923,
349. 432, 233.
264. CHEBBTJLIEZ and RILLIET, HeIv. 296. W E I L A N D and KOBALEE:, ibid., 4 3 3 ,
CHm. Acta, 1932, 15, 856. 267.
265. SMALL and BBOWNING, J. Org. Chem., 297. A C H and KNOBB, Ber., 1903, 36,
1939,3, 618. 3067.
266. PSOHOBB, Ber., 1906, 39, 3130. 298. MERCK AND CO., D. B.-P. 408,870
267. SKITA a n d FBANCK, ibid., 1911, 44, (1923); Frdl. 14, 1303.
2862. 299. F I N D L A Y a n d SMALL, J.A.C.S., 1950,
268. OLDENBEBG, D. B.-P. 260,233 (1911); 72, 3247.
Frdl. 11, 996; Eouben, 4, 58. 300. MEBOK AND CO., D. B.-P. 421,217
269. MANNIOH and LOWENHEIM, Arch. (1923); Frdl. 15, 1515.
Pharm., 1920, 258, 295. 301. K N O B B , Ber., 1906, 39, 1409.
270. TAKAGI a n d U E D A , J. Pharm. Soc. 302. ScHOPP and H I B S C H , Ann., 1931,
Japan, 1936, 56, 44. 489, 224.
271. VAN DTJIN, R O B I N S O N , and SMITH, 303. MEBCK AND CO., D. B.-P. 415,097
J.C.S., 1926, 903. (1923); Frdl. 15, 1518.
272. K N O L L AND CO., D. B.-P. 278,111 304. RAPOPOBT, NAUMANN, B I S S E L L , and
(1913); Frdl. 12, 747; Houben, 4, B O N N E E , J. Org. Chem., 1950, 15,
382. 1103.
273. SMALL, F I T C H , and SMITH, J.A.C.S., 305. K N O K B and H O E L E I N , Ber., 1907, 40,
1936, 58, 1457. 4889.
274. GOTO, Proc. Imp. Acad. (Tokyo), 306. HOLMES and L E E , J.A.C.S., 1947,
1040, 16, 403. 69, 1996.
270. and A B A I , Ann., 1941, 547, 194. 307. K N O B E and SCIINEIDEB, Ber., 1906,
270. Sonoi'ir and WINTMBKALDEB, ibid., 39, 1414.
1027,452,2!W. 308. awl HftninoiN, ibid. 3252.
277. HoioiiiUNauii, JiHi. VaL 2WVI04 (H8 300. FHUiioiiit niid .IOrNiiioMc, ibid., 1907,
May 1020). 40, 1080. '
OH. I V C O D E I N E AND I T S I S O M E E S 95
310. K N O B B and HOBLEIN, ibid. 2042. 342. OOHIAI a n d NAKAMUBA, ibid., 1939,
311. MACDONALD a n d CHECHACK, J.A .0.S., 72, 684.
1948, 70, 1972. 343. Proc. Imp. Acad. (Tokyo),
312. FKEtTND a n d SFEYER, J. pr. Ghem., 1938, 14, 134.
1916, 94, 135. 344. K N O L L AND CO., D. R.-P. 175,068
313. D. R.-P. 296,916 (1916); (1905); Frdl. 8, 1159; Houben, 2 ,
Frdl. 13, 880. 661.
314. U.S. Pat. 1,468,805 (25 345. K N O B B , HOBLEIN, and STATJBACH,
Sept. 1923). Ber., 1909, 42, 3511.
315. LtTTZ and SMALL, J. Org. Ghem., 1939, 346. CAUSSE, J. Pharm., 1899 (6), 9, 378.
4, 220. 347. SMALL a n d MALLONEB, J. Org. Chem.,
316. CAHN and ROBINSON, J.G.8., 1926, 1947, 12, 558.
908. 348. F B E U N D a n d S P E Y E B , Ber., 1 9 1 0 , 4 3 ,
317. GOTO and A B A I , Bull. Ghem. Soc. 3310.
Japan, 1942, 17, 113. 349. MOSSLEB and TSCHEBTJLL, ibid.,
318. DiBTBBLH a n d DICKENS, Arch. 1911,. 44, 105.
Pharm., 1926, 264, 257. 350. F B E U N D , Chem. Ztg., 1911, 3 5 , 648.
319. K N O L L AND C O . , D. R.-P. 365,683 351. and SPEYEB, Z. angew. Ghem.,
(1921); PnK. 14, 1301. 1911,24, 1122.
320. D. R.-P. 380,919 (1922); 352. D I E L S a n d F I S C H E R , Ber., 1916, 4 9 ,
Frdl. 15, 1302. 1721.
321. . Arch. Pharm., 1923, 2 6 1 , 353. H O F F M A N N - L A ROCHB AND C O . ,
140. JD. R.-P. 286,743 (1914); Frdl. 12,
322. D . R..P. 607,931 (1934); 741; Houben, 4 , 588.
Frdl. 2 1 , 652. 354. VON B B A U N , Ber. 1914, 4 7 , 2312.
323. D. R.-P. 617,238 (1934); Frdl. 355. H O F F M A N N - L A ROCHE AND C O . ,
22, 583. D. R.-P. 289,273 (1914); Frdl. 12,
324. D. R.-P. 623,821 (1934); Frdl. 745; Houben, 4, 663.
22, 584. 356. VON B B A U N , Ber., 1916, 49, 750.
325. W E I S S a n d W E I N E B , J. Org. Ghem., 357. D I B L S a n d F I S C H E B , ibid., 1914, 4 7 ,
1949, 14, 194. 2043.
326. VONGEBICHTEN, Ann., 1897,297,204. 358. a n d FBITZSCHE, ibid., 1911, 44,
327. S P E Y E B and R O S B N F E L D , Bar., 1925, 3018.
58, 1110. 359. a n d PAQUIN, ibid., 1913, 4 6 ,
328. SMALL and TUBNBULL, J.A.G.S., 2000.
1937, 59, 1541. 360. S P E Y E B and W A L T H E B , ibid., 1930,
329. B B O W N , Ann., 1854, 92, 325. 63, 852.
330. PELLETIER, Ann. Ghim. Phys., 1836 361. VON B B A U N , ibid., 1916, 49, 977.
(2), 6 3 , 164. 362. H O F F M A N N - L A ROCHE AND C O . ,
331. ANDERSON, Edinburgh, New Phil. J., D. R.-P. 289,274; (1914); Frdl. 12,
1851, 50, 103. 745; Houben, 4, 664.
332. HAIDINGEB, Pogg. Ann. der Physih, 363. VON B B A U N and SOHIBMACHEB, Ber.,
1850 (4), 80, 553. 1923, 56, 538.
333. JOBGENSEN, J. pr. Ghem., 1870 (2), 364. KTJHN, a n d SIDDIQUI, ibid., 1926,
2, 433. 59, 1081.
334. Ber., 1869,2, 460. 365. and K U H N , ibid., 1927,60, 2551.
335. ANDEBSON, Ann., 1850, 7 5 , 80. 366. and K I N D L E S , ibid., 1916, 4 9 ,
336. VONGEBICHTEN and W E I L I N G E R , Ber. 2655.
1905, 38, 1857. 367. R E I D E L - D E H A E N , D. R.-P. 488,610
337. W E I L A N D a n d K A P P E L M E I E E , Ann., (1925); Frdl. 16, 2492.
1911,382,306. 368. POHL, Z. expt. Path. Therap., 1915,
338. F E B B E I N , Schweiz. Wochsckr., 1913, 17, 370.
5 1 , 1. 369. VON B B A U N a n d L E M K E , Ber., 1922,
33. .FaEtTND a n d S P E Y E B , Ber., 1911, 44, 55, 3536.
2339. 370. ibid., 1919,52, 1999.
.'MOTAou, KNOBB, LINGENBBINK, and 371. SPEYEB and Popp,ibid., 1926,59,390.
HOBLEIN, ibid., 1919, 42, 3503. 372. and R O E L L , ibid., 1930, 63, 539.
!Ml. SPIOYIOII a n d WJHTJOHS, ibid,, 192J, 373. ibid., 1929, 62, 209.
54, 2070. 374. FMiiUND, ibid., 1000, 38, 3234.
96 CODEINE AND ITS ISOMEES OH. i v
375. CHBBBtrLiBZ a n d ABAQTJI, HeIv. 404. MANNIOH and SCHULTE, Arch. Pharm.,
CHm. Acta, 1943, 26, 2251. 1938, 276, 593.
376. LTJTZ a n d SMALL, J.A.O.S., 1935, 5 7 , 405. F B E U N D a n d H O L T O J T , Ber., 1899,
2651. 32, 168.
377. E A B B W . VOBM. L U C I U S AND BBTJNING, 406. K N O B K and HOBLEIN, ibid., 1907,40,
D. R.-P. 89,963 (1896); Frdl. 4 , 3341.
1246 -,Houben, 1, 468. 407. and GBIMME, ibid., 3844.
378. SCHMIDT, Ber., 1875, 8, 1267. 408. SPKYER and W I E T E E S , ibid., 1921,54,
379. CAZENEUVE, Compt. Bend., 1891,113, 2647.
747. 409. SMALL and F A B I S , J.A.C.S., 1935,
380. GADAMBB and KNOOH, Arch. Pharrn., 57, 364.
1921, 259, 135. 410. K N O B R and H A W T H O B N E , Ber., 1902,
381. D I B L S and H A N S E N , Ber., 1926, 59, 35, 3010.
2555. 411. PSOHOBB and DICKHAUSEB, ibid.,
382. SKITA a n d K E I L , D. B.-P. 638,757 1912, 4 5 , 1567.
(1934); Frdl. 2 3 , 565. 412. MBEOK, Arch. Pharm., 1891,229,161.
383. HINSBEEG, D. B.-P. 377,588 (1922); 413. ABMSTBONG, J.C.S., 1871, 56.
Frdl. 14, 1303. 414. Ann., 1871, 159, 391.
384. BOEHEINGEB-SOHN, D. B.-P. 270,575 415. O P P B , Ber., 1908, 4 1 , 975.
(1912); JYdZ. U , 995; Ho&en,4,262. 416. K N O B R and H O B L E I N , ibid., 1907,40,
385. H U G , U.S. Pat. 1,069,954 (12 Aug. 2032.
1913). 417. P S O H O B B and BTISCH, ibid., 1995.
386. K N O L L AND C O . , D. B.-P. 239,313 418. K N O B B , D. B.-P., 224,347 (1908);
(1910); Frdl. 10, 1223; Houben, 3 , Frdl. 10, 1222.
678. 419. and R O T H , Ber., 1911,44, 2754.
387. G E S . FIJB CHEM. I N D . B A S E L , D. B.-P. 420. a n d HABTMANN, ibid., 1912, 4 5 ,
322,335 (1916); Frdl. 13, 8 7 5 ; 1354.
Houben, 5, 148. 421. LTJTZ and SMALL, J.A.C.S., 1932, 54,
388. D. B.-P. 330,814 (1917); Frdl. 4715.
13, 878; Houben, 5, 210. 422. SMALL and LTJTZ, ibid., 1934,56,1928.
389. Soo. A N O N . I N D . CHIM. A B A L E , Swiss 423. LTJTZ a n d SMALL, ibid., 56, 1741.
Pat. 76,996 (1918). 424. B E N T L E Y , R O B I N S O N , a n d W A I N ,
390. SKITA a n d K B I L , D. B.-P. 620,998, J.C.S., 1952, 958.
(1933); .FVdZ. 22, 585. 425. K N O B B a n d W A E N T I G , Ber., 1907,
391. TBOPONWEBKE DBINKLAGE AND C O . , 40, 3860.
D. B.-P. 627,565 (1933); Frdl. 22, 426. SMALL a n d LTJTZ, J.A.C.S., 1935, 5 7 ,
589. 361.
392. SKITA, JD. B.-P. 648,259 (1935); Frdl. 427. MOBBIS and SMALL, ibid., 1934, 56,
24, 357. 2159.
393. RAKSHIT, J.C.S., 1918, 466. 428. K N O B B , BTJTLEB, a n d H O B L E I N , Ann.,
394. LEEOY. Compt. Bend., 1899,129, 220. 1909, 368, 305.
395. Ann. CHm. Phys., 1900 (7), 2 1 , 429. . . a n d H O B L E I N , Ber., 1906, 39,
87. 4412.
396.. HARTLEY, Phil. Trans. Boy. Soc, 430. H O B L E I N , a n d STATJBAOH, ibid.,
1885, 176, 471. 1909, 42, 3521.
397. KITASATO, Acta Phytochim., 1927, 3 , 431. LTJTZ a n d SMALL, J.A.C.S., 1934,56,
175. 2466.
398. GOMPEL a n d H B N B I , Compt. Bend., 432. WILSON, Pharm. J. Trans., 1923,110,
1913, 157, 1422. 363.
399. STBINEB, Bull. Soc. Chim. Biol., 1924, 433. ibid., 1924, 113, 688.
6,231. 434. MABTIN, J. Pharm. Chim., 1922 (7),
400. BBUSTIEB, Bull. Soc. Chim., 1926 (4), 26, 176.
39, 1527. 435. DOTT, Pharm. J. Trans., 1884 (3),
401. EiNDLAY and SMALL, J.A.C.S., 1950, 14, 917.
72, 3249. 436. ibid., 973.
402. SMALL and RAPOPORT, J. Org. Chem., 437. B 6 D E K B B , Ann., 1849, 7 1 , 63.
]947, 12,284. 438. H o w , Chem. Zent.., 1855, 93.
4011. ~-~- TuiiNiWLr,, and Yifuti, ibid., 439. 'KtIANQO[S and BI.ANO, Cornet. Bend.,
101)8, 3 , 204. 1922,176, JOI).
CH. I V C O D E I N E AND I T S ISOMERS 97
440. FBANCOIS and BLANC, Bull. Soc. 454. L E I , J. Am. Pharm. Assoc., 1938, 2 7 ,
Chim., 1922 (4), 3 1 , 1208. 393.
441. ibid. 1304. 455. SHA, M A , a n d H o o , Sci. Repts. Natl.
442. THOMSEN, Chem. Abs., 1911,5, 3417; Tsinghau Univ., [A] 1934, 2 ,
Chem. Zent., 1911, i. 1515. 245.
443. CHATTAWAY and PARK.ES, J.C.S., 456. K H A L E T S K I I a n d GEBSHENTSVIT, J.
1930, 1003. Gen. Chem. (U.S.S.R.), 1947, 17,
444. POMMEREHNE, Arch. Pharm., 1898, 2066.
236, 479. 457. SCHAEFEE, J. SOC. Chem. Ind., 1910,
445. D A N E T , J. Pharm. OHm., 1928 (8), 29, 928.
7, 548. 458. U.S. Pat. 963,254 (1910).
446. J A N O T and CHAIGENEATJ, Corrupt. 459. T 6 G E and L I N D E , Arch. Pharm.,
Bend., 1949,228, 1152. 1901, 239, 121.
447. CARLSOHN and NEUMANN, J. pr. 460. K N O B B , Ber., 1894,27, 1144.
Chem., 1936 (2), 147, 38. 461. E D D Y , J. Pharmacol., 1933, 4 9 ,
448. FLORENCE, Bull. Soc. Chim., 1927 319.
(4), 4 1 , 1097. 462. PSOHOEB, Ber., 1906, 39, 3130.
449. P O E and STRONG, J.A.C.S., 1935, 37, 463. E D D Y and SMALL, J. Pharmacol.,
380. 1934, 5 1 , 35.
450. MEBING, U.S. Pat., 629,264 (1899). 464. H I L L , Dissert. (Frankfurt am Main),
451. M E B O I E B and DETBIE, J. Pharm. 1925.
Chim., 1940 (9), 1, 287. 465. S P E Y E R a n d B E C K E R , Ber., 1922, 5 5 ,
452. DAOOOMO, Jahresber. Fortschr, Chem., 1329.
1884, 1385. 466. E D D Y , J. Pharmacol., 1935, 5 5 ,
453. MAPLBTHOBPE and E V E E S , Pharm. J. 127.
Trans., 1925, 1 1 5 , 137. 467. and H O W E S , ibid. 257.
IUl.I Il
V
PORPHYROXINE
MERCK [1] in 1837 and Robertson [2] later isolated from Bengal opium
a substance they named porphyroxine, but this was clearly not a single
compound and was believed by Hesse [3] to be a mixture of rhoeadine,
meconidine, and other alkaloids, and indeed it resembles rhoeadine in
its properties and method of preparation [4]. Dey [5] also reported the
preparation from opium of a substance that gave a violet colour with
mineral acid, a reaction cited by Merck [1] as characteristic of porphy-
roxine.
In 1919 Rakshit [6] isolated a substance that he claimed was pure
porphyroxine, and that he believed was the main component of Merck's
preparation. The substance was obtained as pale yellow or colourless
prisms, m.p. 134-135 C, and gave the following colour reactions:
Reagent Colour
cone. H 2 SO 1 . . . . red
cone. H 2 S O 4 + t r a c e K 2 Cr 2 O, grass green
eonc. HNO 3 . . . . pale yellow
cone. HCl . . . . orange
iodine solns.+base . orange-red ppt.
iodine solns.+base in dil. HCl . brick red ppt.
Me(X / ^ MeQ
CH3
M^CO^(J) (t>-M^coA<l>
porphyroxine and led him to suggest that the latter was in fact only-
impure codeine, and to draw attention to the fact that Rakshit did not
report having found codeine during the isolation of porphyroxine.
It must be concluded, therefore, that it is very likely that no such
alkaloid as porphyroxine exists and that whilst the preparations of
Merck [1] and Robertson [2] are clearly mixtures, the so-called pure
alkaloid isolated by Rakshit was very probably a mixture of bases [11]
containing a considerable amount of codeine [9].
Solvent
for Crystal Specific
0
Compound m.p. O. reorystn. form rotation Temp. Solvent Refs.
Porphyroxine . . . . 134-135 prisms -139-9 32 CHCl3 6
hydrochloride . 155 H2O needles -118-8 32 H2O 6
hydrobromide . 148-150 H2O needles -90-6 32 H2O 6
hydriodide 115 powder -77-8 32 BtOH 6
aurichloride amorph. 6
platinichloride D. 204 H1O powder 6
nitrate 122 H2O tablets -115-4 32 H2O 6
-sulphate . 193 H2O plates -111-4 32 H2O 6
phosphate 117 H2O powder -98-2 32 H2O 6
oxalate 182 H2O prisms -114-2 32 H2O 6
citrate 82-85 amorph. -108-6 32 H2O 6
-tartrate 116-118 -95-5 32 H2O 6
picrate 198 -49-9 32 H2O 6
methochloride . c. 171 -90-4 34 H2O 7
methiodide 150-152 amorph. -82-5 25 MoOH 7
methomethylsulphate 205 MeOH needles -74-6 25 MeOH 7
methohydroxide 112-115 BtOH cubes -71-8 34 BtOH 7
oxime c. 198 Bt2O 7
phenylhydrazone 15Od. acetone 7
semicarbazone . D. 244 7
Acetylporphyroxine 125 benzene -187-2 34 BtOH 7
hydrochloride . 126 H2O needles -123-4 30 H2O 7
hydrobromide . c. 155d. H2O needles -98-8 35 H2O 7
hydriodide 104-107d. EtOH needles 7
sulphate . D. c. 190 H2O needles -150-2 34 EtOH 7
platinichloride . 230d. 7
Methylporphyroxine 125-126 benzene needles -131-8 28 CHCl2 7
oxime 185-186 MeOH 7
phenylhydrazone 189d. amorph. 7
semicarbazone . 2l7d. 7
Methyltetrahydroporphyroxine 150 MeOH plates 7
oxime 234-235 7
phenylhydrazone 126 7
semicarbazone . D. c. 210 7
B I B L I O G R A P H Y TO C H A P T E R V
1. M E R C K , Arm., 1837, 2 1 , 201. 11. MACHIGTJCHI, J. Pharm. Soc. Japan,
2. BOBEBTSCW, J. Pharm., 1852 (2), 2 2 , 1926, 592, 19.
190. 12. BAKSHIX, Analyst, 1921, 46, 485.
3. H E S S E , Ann., 1870, 153, 47. 13. BAMFOBD, ibid., 1930, 55, 445.
4. Ann. Suppl, 1865-6, 4, 50. 14. A L L E N a n d GATES, J.A.G.8., 1942,64,
5. D E Y , Pharm. J., 1882, 12, 397. 2120.
6. R A K S H I T , J.G.S., 1919, 455. 15. . ibid. 2123.
7. Ber., 1926, 59, 2473. 16. ibid. 2439.
8. PSOIIOBB, JAJSCICEL, a n d ITEOHT, ibid., 17. F B E U N D a n d S P E Y E B , Ber., 1910, 4 3 ,
1902, 35, 4377. 3310.
9. RAJACKU-ALAN, J. Org. Ohem., 194C, 18. Moss MIR and TSOHEBTJKL, ibid., 1911,
10, 175. 44, 100.
10, . Cfrww A1Ot., 1048, 12, 24.
VI
THE CODEIMETHINES AND THEIR
DERIVATIVES
T H E quaternary salts of codeine and its isomers can be degraded to
unsaturated bases to which the general term 'methylmorphimethine'
has hitherto been applied, b u t here the less cumbersome and more
systematic term ' codeimethine' [1] will be used, the term methyl-
morphimethine being reserved for the derivatives obtained from nuclear
methylated morphines. The term dihydromethine will be applied to
bases in which the double bond introduced by degradation has been
saturated. I n this way a convenient and unambiguous system of nomen-
clature is available.
The reaction between silver oxide and the quaternary salts of
morphine and codeine was first investigated, inconclusively, by How
[2]. Grimaux, by heating codeine [i] methiodide with silver oxide or
potassium hydroxide, obtained a-codeimethine [ n ] ; dionin methine
likewise could be prepared from dionin (ethyl morphine) methiodide
[3-4]. The reaction presumably proceeds by elimination of water from
the methohydroxide, and Hesse found t h a t evaporation of codeine
methohydroxide solutions over concentrated sulphuric acid affords
a-codeimethine [5].
Morphine methiodide [in] cannot be induced to degrade in this way
owing to formation of the phenol betaine [iv], from which water cannot
be eliminated [6].
a-Codeimethine [n] when heated alone [7], with water, 50 per cent,
alcohol, or, best, alcoholic potassium hydroxide [8] is converted into an
isomer, ^-codeimethine [v], by migration of the 7:8 double bond into
conjugation with t h a t at 9:10. These structures [n] and [v] for the -
iirui ^-isomers receive support from the ultra-violet absorption spectra
of the bases, shown in Fig. 2 in comparison with those of codeine [i],
ougenol [vi], and isoeugenol [vu], and in Pig. 3 in comparison with
102 THECODEIMETHINESANDTHEIRDEBIVATIVES OH. VI
MeO-. MeO^
MeO' CH
0 Il
CH CH
.JSTMe2 / -^NMe2
CH 5 CH3
HO' HO
[V] [VI] [VII] [VIII]
MeO
NMe91
4-5,
r I I
---a-CODEIMETHINE (E) EUGENOL(VI)
o--oCODEINE (I)
4O
\ "^v' .-'-. ^-
* V ^' \ \ - X X
~\ \ '<A
\ V \\
3
\ i '., \ i
g3-35
\ 1 /"\ 'V- I
\ v" //v
iIl i\ '
3O-
~
' ' i >
\/
V
I
111
l
2-5
25OO
I 3000
Ii I i 35OO
i
WAVELENGTH A
FlO. 2.
OH. vi THE CODEIMETHINES AND T H E I R D E R I V A T I V E S 103
WAVELENGTH A
FIG. 3.
HALOGENATED CODEIMETHINES
1-Bromocodeine can be degraded to 1-bromo-a-codeimethine [44-45],
which can be converted to the /J-isomer [46] and degraded to 1-bromo-
methylmorphenol [32] and 1-bromoacetylmethylmorphol [44-45]. The
latter has been converted to l-bromo-3:4-dimethoxyphenanthrene,
identical with an authentic specimen [45].
Bromination of a-codeimethine in chloroform affords 'bromohydroxy-
dihydro-a-codeimethine', C 19 H 24 O 1 NBr, which on acetolysis gives
J -bromo-3-methoxy-4-acetoxyphenanthrene, though the acetyl deriva-
tive is reported to give 3-methoxy-4:6-diacetoxyphenanthrene under
the same conditions [46]. As an intermediate in the latter degradation
' acetylnorparathebaine methobromide' was obtained and converted to
'norparathebainemethiodide', C 19 H 22 O 3 NI [47]. Acetyl-a-codeimethine
is brominated in the same way in chloroform or dilute acetic acid, but
in glacial acetic acid it gives 'acetyldibromodihydro-a-codeimethine',
CjJ1I-I25O4NBrJj, which on boiling with acetic anhydride yields 'acetyl-
bromoMO-a-codoimothme', CjJ1L-Iu4O4NBr, [46].
106 THECODEIMETHINESANDTHEIRDERIVATIVES OH. VI
R E D U C T I O N OF THE CODEIMETHINES
Three a-dihydrocodeimethines have been prepared as follows:
(i) a - D i h y d r o c o d e i m e t h i n e - A (codeine dihydromethine) [vin], which
results from the reduction of a-codeimethine by sodium, liquid ammonia,
and alcohol. The yield is below 50 per cent, owing to the formation of
phenolic substances, presumably of the dihydrodesoxycodeine type.
I t cannot be prepared by the sodium-ammonia reduction of codeine
methiodide, which apparently gives dihydrodesoxycodeine-C dihydro-
methine [9] (see Chaps. IV and IX).
(ii) a - D i h y d r o c o d e i m e t h i n e - B (neopine dihydromethine) [ix], ob-
tained by the sodium-alcohol reduction of a-codeimethine [29, 49] which
involves prior rearrangement to the /3-compound, the mild catalytic
[50] or sodium amalgam [51] reduction of /3-codeimethine, and the
reduction of neopine methiodide [xn] by sodium and liquid ammonia
[52]. The latter reduction and its failure to undergo isomerization serve
to fix its structure as [ix]. The methyl ether results from the mild
catalytic hydrogenation of /3-codeimethine methyl ether [53].
(iii) a - D i h y d r o c o d e i m e t h i n e - C (dihydrocodeine methine) [x] is
formed by the mild catalytic hydrogenation of a-codeimethine [50]
and the Hofmann degradation of dihydrocodeine [xvm] [54-56]. The
ultra-violet absorption spectrum shows the presence in [x] of the same
conjugated system as in a-codeimethine, whilst the spectra of [vin]
and [ix] show no conjugation in these compounds (Fig. 3). [x] is also
obtained when a-codeimethine is boiled with Raney nickel in alcohol,
together with dihydrocodeinone methine [xix] [9], the latter arising
from a rearrangement of a-codeimethine similar to the isomerization of
codeine to dihydrocodeinone under the influence of noble metal catalysts
[57-62] (see Chap. IV). The C-6 epimer of [x], i.e. y-dihydrocodei-
methine-C (dihydroisocodeine methine), results from the Hofmann de-
gradation of dihydroisocodeine [55].
Vongerichten [46] reported the bromination of a dihydrocodeimethine
of unspecified origin to a-bromodihydrocodeimethine (m.p. 165 C.)
and the isomorization of this to a /3-compound (m.p. 169 C ) . I t seems
probable that those two supposed isomors aro idontioal as there is no
CH. v i THE CODEIMETHINES AND T H E I R DERIVATIVES 107
H;/PtOj
ON HYDRO-
"OH "OH CHLORIDE
IN HOAc
-Jr-CODEINE C-CODEIMETH1NE
CXIII)
IH^PtO,
I ON HYDROCHLORIDE
JN HOAc. MoO MeO
McO.
^NMc NMe1
1
"OH "OH ^ ^/- 1 -OH
DIHYDRO-^-CODEINE-A DIHYDRO-e- f. TETRAHYDRO-e-
CODEIMETHINE-A ( j CODEIMETHINE-A
(XXIIl) (XXIV) (XXIl)
Z
4H
O
O NMe
Z)
Q
UJ "on
or DIHYDRO --^-CODEINE - B DIHYDRO-e-
LL) CODEIMETHINE-B
(XXV) (XXVI)
Q.
O
U
NMe NMe1
^OH OH
DIHYDRO-^-CODEINE-C DIHY DRO-e HEXAHYDRO-e-
CODEIMETHINE CODEIMETHINE
(XXVIIl) (XXIX) (XXVII)
^y
MeO MeO
NMe NMe2
"on "OH
TETR AHYDRO - ^ - TETRAHYDRO-e-
CODEINE CODEIMETHINE-C
(XXX) (XXXI)
OH. vi THE CODEIMETHINES AND T H E I B D E R I V A T I V E S 109
6-METHYLCODEIMETHINES
When codeinone [xxxv] is treated with lithium methyl a nearly
quantitative yield of one isomer of 6-methylcodeine [xxxvi] is obtained,
and this can be degraded to 6-methyI-a-codeimethine [xxxvn], which
can be isomerized to 6-methyl-j6-codeimethine [XXXVIII]. Dry distilla-
tion of the methohydroxide of [xxxvn] affords 6-methylmorphenol
methyl ether [xxxix] [69].
Similarly, treatment of dihydrocodeinone with lithium methyl affords
6-methyldihydrocodeine [XL], which can be degraded to 6-methyl-
dihydrocodeine methine [XLI] and 6-methyl-6-hydroxy-13-vinylhexa-
hydromethylmorphenol [XLII, R = C H = C H 2 ] , the latter giving
6-methyl-6-hydroxy-13-ethyloetahydromethyl morphenol [XLII, 9:10-
dihydro, R = E t ] on reduction [70].
ACETOCODEIMETHINES
Hofmann degradation of 1-acetocodeine [LXI] (see Chap. IV) leads
readily to 1-aceto-^-codeimethine [LXII] [79], the a-isomer [LXIII] only
being obtained if the degradation is stopped after five minutes [80].
The /3-isomer can be degraded to 1 -acetyl- 3-methoxy-4-hydroxyphenan-
threne by heating with sodium ethoxide at 160 C. [79]; the metho-
hydroxide of [LXII] on dry-distillation affords 1-acetylmethylmorphenol
[LXIV], though on heating in cycfo-hexanol with sodium cyclohexoxide an
undistillable oil giving no semicarbazone is obtained, probably as the
result of a polymerization reaction involving the ketone group [80].
Attempts to prepare [LXIII] and [LXII] by the nuclear acetylation of
oc- and /2-codeimethines failed [80].
9 (or 10)-KETODIHTDBOOODEIMBTHIHB
Oxidation of codeine with cold chromic acid and sulphuric acid gives
rise to a hydroxycodeine [81] (see Chap. IV) in which the new hydroxyl
group is at position 9 or 10, as degradation gives a methine base [LXVI]
[82] t h a t on acetolysis is converted to 3-methoxy-4:9 (or 10)-diacetoxy-
phenanthrene [LXVII ?] [82] which loses an acetoxy group on oxidation
to a quinone [LXVIII] [83]. As the methine base [ L X V I ? ] is a ketone
[84, 85] the carbonyl group must arise from [LXV] by tautomerization,
OZONOLYSIS OE D l H Y D B O CODEINE M E T H I N E
Rupture of the aromatic nucleus with production of an aldehydo-
ester, 7:8-dihydrocodizal-3-methyl ester methine [LXIX], occurs when
dihydrocodeine methine [x] is treated with ozonized oxygen in aqueous
acid solution. The hydroxyl group of [x] presumably remains intact, as
an acetyl ester of [LXIX] can be prepared, and oxidation with chromic
acid leads to 6-keto-7:8-dihydrocodizonal-3-methyl ester methine [LXX]
which no longer yields an acetyl derivative, [LXIX] can be hydrogenated
to a dihydro-derivative [87]. I t is surprising t h a t in the ozonolysis of
dihydrocodeine methine rupture of the aromatic nucleus at the 2:3
bond occurs, whereas with dihydrocodeine rupture occurs at the 3:4
bond (see Chap. IV).
D E B I V A T I V E S OB M O E P H I M E T H I N E
As already stated, morphine methiodide cannot be induced to
undergo Hofmann degradation owing to the formation of a phenol
botaine [6]; nor can a morphimethine derivative be obtained by the de-
methylation of a- or /3-codeimethine, which gives only tars [51].
However, a-dihydrocodeimethine-B (neopine dihydromethine) [ix] can
be demethylated by 16 per cent, hydrobromic acid in glacial acetic acid
Lo give the alkali soluble 6-acetyldihydromorphimethine, which can be
hydrolysed to dihydromorphimethine. Methylation of the latter, how-
over, does not reproduce [ix], but an isomer t h a t gives a-tetrahydro-
codoimethine on reduction, so movement of the double bond must occur
during the demethylation.
6-Acetyldihydromorphimethine can be hydrogenated to 6-acetyl-
totrahydromorphimethine [LXXI, R = Ac], which is insoluble in alkali
doHpito having a free phonolic hydroxyl group, [LXXI, R = Ac] can also
bo pcopurod by tho domothylation of a-totrahydrooodeimethine. I t can
116 T H E C O D E I M E T H I N E S AND T H E I E D E R I V A T I V E S OH. VI
be hydrolysed to tetrahydromorphimethine [LXXI, R = H ] , identical
with the product of reduction of dihydromorphimethine. The medium
of demethylation is important, as attempts to effect the reaction with
48 per cent, hydrobromic acid gave only t a r s ; evidently acetylation
precedes demethylation [51].
Vongerichten reported the isolation, as a by-product in the prepara-
tion of 3:4-diacetoxyphenanthrene by heating diacetyl-morphine
with silver acetate and acetic anhydride at 180 C , of a /?-morphi-
methine t h a t could be methylated to /3-codeimethine methiodide [88].
Repetition of this work revealed the product to be a monoacetylated
/3-morphimethine t h a t can be methylated and hydrolysed to /3-codei-
methine, and reduced to [LXXI, R = Ac] [51].
STABILITY OF THE N I T R O G E N R I N G I N C O D E I N E
The stability of the nitrogen-containing ring of codeine, compared
with t h a t of other cyclic bases, has been investigated by von Braun in
an ingenious way [89].
The secondary base norcodeine [LXXII] on treatment with penta-
methylene di-iodide gives the salt [LXXIII] in which the nitrogen atom is
common to the codeine ring and a piperidine ring. 'Norcodeinium-
piperidinium iodide' [LXXIII] suffers degradation t o ' codeimethylpiperi-
dine' [LXXIV], the acetate of which is converted by cyanogen bromide
to e-bromoamylcyano-acetylcodeimethylamide [LXXV]. The latter is
readily deacetylated and exchanges its bromine for basic residues, - 0 ^ ,
etc. Dihydronorcodeine yields the dihydroderivatives of [LXXIII] and
[LXXIV].
Similarly co:a/-dibromoxylene and norcodeine give norcodeinium-
dihydroisoindolinium bromide [LXXVI] which can be converted t o
codeimethyldihydroisoindole [LXXVII] and w-bromoxylylcyanoacetyl-
codeimethyl-amide [LXXVIII], whilst norcodeinium-morpholinium iodide
[LXXIX] (from norcodeine and /?: /5'-di-iododiethyl ether) can be degraded
to codeimethylmorpholine [LXXX]. In all these cases, therefore, the
codeine ring was broken in preference to the other heterocyclic ring,
presumably owing to the activating influence of the codeine aromatic
nucleus.
AoO HO
[LXXVII]
MeO
HO
[LXXVIII] [LXXIX]
MeQ
HO
[LXXX]
Solvent
for Crystal Specific
Compound m.p. 0. reorystn. form rotation Temp. Solvent Refs.
iv-rodeimethlue . . . . 118-5 BtOH/ prisms -212 17 BtOH 4, 5, 14
HaO
hydrochloride-2H 2 O . 105 HaO needles 5
porohlorate . . . . 183 95% prisms -116-4 20 HVO 9
BtOH
l>liiXlnichloride-HaO . yellow
cryst.
138 -112-8 17 H2O 16
Iiu'l.ntto . . . . . 165 14
/-112 99% 19
BtOH
mulhlodldo . . . . 245 I-94-56 17 99% 14
EtOH
iiuiMinohloride . . . . 5
N-oxldo D. 188 H2O 63
A(inlr.vl-i.(!odoimotMno . 66 H2O -96-3 17 99% 5,14, 33
BtOH
11(11.J1I.0 . . . . 5,14, 33
mulhlodldo . . . . 207 -73-8 17 EtOH 14
mi'Uiolirniuldn . . . . 207-208 34
lliiKoyl-ii-ii()il(iliuotliIno . 182-183 87
imil.lilodUlo . . . . 188 .. ,. 37
118 T H E C O D E I M E T H I N E S AND T H E I R D E R I V A T I V E S OH. vi
Solvent
for Crystal Specific
Compound m.p. 0 O. recrysln. form rotation Temp. Solvent Refs.
<*-codeimethine methyl ether . 94 MeOH needles -251-9 24 MeOH 38
petrol
methiodide . . . . 256 -134-4 23 H2O 38-39
ct-codeimethine carbanilide 122-3 needles 14
methiodide . . . . 251 14
/9-codeimethinc . . . . 134-135 BtOH prisms + 438 17 BtOH 14
benzoate . . . . . 157 EtOH + 254 17 H2O 7-8
/ + 247 19 90% 7-8
methiodide . . . . 300-303d. EtOH
j+262 21 90% 12
EtOH
Acetyl-j3-codoimethine amorph. + 413-9 17 EtOH 14
methiodide . . . . amorph. + 257-6 17 EtOH 14
Eormyl-P-codoimethine . 36
,8-codeimethine methyl ether . 82 petrol + 432 17 38
hydriodide . . . . D. 243 38
methiodide . . . . /+268-5 22
318-320 22 H2O 38, 39
1+278-5
y-codeimethine . . . . 167-169 tablets + 64-3 20 OHCl3 15
hydrochloride . . . . cryst. 15
hydriodide . . . . 238-239 + 37 20 H2O 35
benzoate . . . . . 100 + 41-3 15 EtOH 16
methiodide . . . . 265 BtOH + 34-7 17 H2O 15
y-codeimethine methyl ether . 41 41
hydriodide HjO 192-193 H1O + 20-3 22 It 2 O 41
methiodide . . . . D. 259 + 14 20 H2O 38-39
8-codeimethine . . . . 111-113 Et 2 O + 256-6 15 MeOH 16
benzoate . . . . . 99-108 H2O + 181-1 15 BtOH 16
methiodide . . . . 282-284 H2O + 150-7 15 BtOH 16
s-codeimethine methyl ether . 71-72 50% plates 41
MoOH
hydriodide . . . . 212 41
methiodide . . . . 286 + 170-9 28 H2O 38
e-codeimethine . . . . 129-130 Et 2 O -120-1 15 BtOH 20
hydrochloride H2O 150 -154 15 H2O 17, 20
hydriodide . . . . 210-213 -95-6 20 H2O 35
methiodide . . . . 196-198 -111 15 H2O 17, 20
Acetyl-e-codeimethine oil 17
methiodide . . . . 205-210 -45 15 H2O 17, 20,
35
c-codeimethine methyl ether . 75 -92-8 18 EtOH 35, 38
hydriodide . . . . 207 -85-5 15 H2O 35, 38
methiodide . . . . 277 -79-4 20 MeOH 35,
38-9
-codeimethine . . . . oil 19
perchlorate . . . . 117-118 H2O -154 28 H2O 68
acid tartrate . . . . 99-101 H2O -126 25 H2O 68
salicylate . . . . 118-120 H2O -141 25 H2O 68
methiodide . . . . c. 180 -148 15 H2O 19
a-Bihydrocodeimethine-A (codeine di-
hydromethine) . . . . oil 9
perchlorate . . . . 210 90% needles -33-4 20 H2O 9
EtOH
methiodide . . . . 265 90% prisms -31-7 20 H2O 9
BtOH
a-dihydrocodeimethine-B (neopine
dihydromethine) 86-88-5 petrol prisms 51
hydrochloride . . . . 235-236 H2O prisms -86-3 24 H2O 51
perchlorate . . . . 216-217 95% prisms -27-7 20 50% 52
EtOH BtOH
benzoate 162-164-5 Bt 2 O plates 51
methiodide . . . . 263 90% prisms -31-3 19 H2O 52
BtOH
methyl ether . . . . oil 53
Acetyl-a-dihydroeodeimethine-B
methiodide . . . . 265 + 76 22 49, 51
a-dihydrocodoimethine-C (dihydro- oil 50, 54,
eodoino mothlno) 56
porolilornl/O . . . . 201-202 50% prisms 9
/ 178
Eton 54
moUilortldo'11,0 1 100 :: ,, ,, ,, ,, 00, 50
OH. vi T H E C O D E I M E T H I N E S AND T H E I R D E R I V A T I V E S 119
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Ternp. Solvent Refs.
a-dihydrocodeimethine-C methiodide
(anhyd.) 223-225 49, 50
y-dihydrocodeimethine-C 151 BtOH prisms 55
methiodide . . . . 269 H8O needles 55
a-tetrahydrocodeimethme oil 54, 63
hydrochloride-2H 2 O . 94 H8O -31-9 H8O 54, 63
hydrochloride (anhyd.) 230-5-232 51
hydriodide . . . . 251d. 63, 54
perchlorate . . . . 218-219 54, 63
nitrate . 174-175 54, 63
platiniehloride . . . . 202 54, 63
methiodide . . . . 220-221 54, 63
Acetyl-a-tetrahydrocodeimethine oil 63
hydrobromide . . . . 230 63
hydriodide . . . . 223 63
methobromide . . . . 225-226 50
a-tetrahydrocodeimethme methyl
ether . . . . . 43-46 53
aurichloride . D. 143 53
methiodide . . . . D. 247 -40 20 Aq/ 53
EtOH
n-tctrahydrocodeimethine-N-oxide-
IJH 2 O 94 63
- - sulphonic acid a 295 63
- - sulphonic acid /3 . . . 270 63
y-tctrahydrocodeimethine 115 50% octa- -29-2 1S d'ii. 63
EtOH hedra HOAc
hydrochloride 3H8O . D. 273 63
- - hydriodide . . . . D. 265 63
- sulphate . . . . . cryst. 63
- methiodide . . . . D. c. 300 63
A cctyl-y-tetrahydrocodeimethine 90-91 63
hydriodide . . . . 220 63
methobromide 3H8O . 100-102 50
I )Ihydro--codeimethine-A oil 65
- - hydriodide . . . . 232-235 EtOH + 99 23 H8O 65
J)lhydro-e-codeimethine-B 188-5- EtOAc + 28 21 CHCl, 66
189-5
Dlhydro-e-codeimethine-O 150 EtOAc + 62-5 23 CHCl, 66
Dlhydo-e-eodeimethine-A methyl 102-5 40% needles + 202 27 EtOH 67
ether EtOH
- hydrochloride . . . . 219-220 EtOH + 157 27 H2O 67
- perchlorate . . . . 85-87 + 136 27 H8O 67
155-156
Dlhydro-e-codeimethine-C methyl 140- acetone + 138-5 25 EtOH 67
other 140-5
Tot rahydro-e-codeimethine-A . oil 65
- hydrochloride . 187 EtOAc needles + 20 23 H8O 65
- - hydriodide 225-226 H2O prisms + 18-6 23 H2O 65
- - salicylate . 198 H2O needles + 18-1 27 H8O 65
- acid tartrate 197-5 H2O plates + 27 27 H8O 65
'i'ol rahydro-e-codeimethine-G 196-197 EtOH prisms + 192 23 EtOH 65
hydriodide 123-124 H8O scales + 156-5 25 CHCl8 65
Totmhydro-e-codeimethine-A methyl 98-5 50% plates + 54 27 EtOH 67
other EtOH
hydrochloride . . . . 251-252 EtOH needles + 42 27 H8O 67
Tctrahydro-E-codeimethine-C methyl 156-5- acetone plates + 199 2> EtOH 67
other 157
i 155 Et 2 O needles 63
I fo.Vtthydro-<;-cadeimethine 166-5- EtOH prisms +28 213 EtOH 65
l 167-5
/ 213 plates 63
hydrochloride . . . . \250-254 EtOH plates + 8-1 23 EtOH 65
iuild tartrate . . . . 114-115 + 15-6 27 H2O 65
Dlncotylhoxahydro-c-codeimethine . oil 63
-methiodide . . . . 255 63
1 loxiihydro-e-codelmothine mothyl
other 138 EtOAo + 17-4 25 EtOH 67
Dlhydra-C-oodolmothino-A 00 HtOAo-I- pyramldB + 117 2> EtOH 68
lluroln
wtlloyliito . J75 WoOH .. -I- 70 23 H9O 08
120 THECODEIMETHINESANDTHEIRDERIVATIVES OH. VI
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Ter np. Solvent Refs.
Tetrahydro--codeimethine-A . 110 EtOAc + needles -26 25 EtOH 68
ligroin
salicylate . . . . . 175-5 HaO 68
Tetrahydro--codeimethine-C .
hydriodide . . . . 249 Ha6 + + 46-7 23 HsO 68
acetone
Hexahyd ro- C-codeimethine 174-175 EtOAc 63
hydriodide . . . . 279-281d. H,0 -39-8 23 H2O 68
6-methyl-a-codeimethine. 106-5- BtOAc prisms -222 23 EtOH 69
107-5
methiodide . . . . 203-5- MeOH+ 69
205-5 EtOAc
6-methyl-/3-codeimethine. 95-5-97 suWim. + 357 23 EtOH 69
methiodide . . . . 283-284 69
6-methyldihydrocodeine methine oil 70
hydrochloride . . . . 241-243 Et,6 + -6-7 23 EtOH 70
EtOH
salicylate . . . . . 198-200 -2-3 23 EtOH 70
methiodide . . . . 269-271 + 8-1 2O EtOH 70
6-methoxy-13-vinylhexahydro-
metrrylmorphenol oil + 61 2O EtOH 40
6-hydroxy-13-vinylhexahydro-
methylmorphenol 102-103 hexane + 77-1 2O EtOH 40
j)-phenylbenzoate 173-174 EtOH + 73-1 2O diox- 40
6-methoxy-13-ethyloctahydro- ane
methylmorphenol 51-52 sublim. -44 2O EtOH 40
6-hydroxy-13-ethyloctahydro-
methylmorphenol oil 40
y-phenylbenzoate 170-172 EtOH -3-4 25 diox- 40
6-methoxy-13-vinyIoctahydro- ane
methylnorphenol 47-49 pentane 40
6-hydroxy-13-ymyloctahydro-
methylmorphenol oil 40
j)-phenylbenzoate 168-170 EtOH + 53-9 2O diox- 40
6-methyl-6-hydroxy-13-vinylhexa- ane
hydromethylmorphenol sublim. cryst. + 24-4 2O EtOH 70
6-methyl-6-hydroxy-13-ethylhexa-
hydromethylmorphenol 98-100 sublim. -29-9 2O EtOH 70
1-aceto-a-codeimethine . 188- EtOH prisms + 12-6 2O ZN- 80
188-5 HOAc
l-aceto-/3-codeimethine . 149 EtOH needles + 150 21 CHCl, 79
6-acetyl-l-aceto-/3-codeimethme
methiodide . . . . 180-182 79
1-bromo-a-codeimethine . 132 and -104-1 15 EtOH 46
182-184
methiodide . . . . -110-7 15 EtOH 46, 47
Acetyl-1-bromo-a-codeimethine
hydrobromide . . . . D. 235 46
hydriodide . . . . D. 222 46
l-bromo-/3-codeimethine . 184 + 128-2 15 EtOH 46
methiodide . . . . amorph. 46
l-bromo-a-dihydrocodeimethine-B ? . 169 46
methiodide . . . . 227 46
1-nitro-a-codeimethine . 215 Hs6 + 44,71
EtOH
1-nitro-a-tctrahydrocodeimethine
nitrate . . . . . 220-221
o-chlorocodeimethine oil 63
hydrochloride . . . . 177-178 63, 37
methiodide . . . . 163 63
a-dichlorocodeimethine 180-181 EtOH needles 37
mothlodido . . . . 153-154 37
a-ohlorodlhydrooodolmothmo-O 103 MeOH 54
mothlodido . . . . 272 EtOH noedlos 54
a-oMoroloUiiliyrtrooodoimotlilno oil 03
liydrnrldortdn . . . . 2(17 3
-liydrnbromldo . . . . 23 08
hytU'lodklo . . . . 28(1
. Oil
en. vi T H E C O D E I M E T H I N E S AND T H E I R D E R I V A T I V E S 121
Solvent
for Crystal Specific
Compound i.p. C. recrystn. form rotation Temp, Solvent
Solvent
for Crystal Specific
Compound m.p. G. recrystn. form rotation Temp. Solvent Refs.
m-bromoxylylcyanoacetylcodeimethyl- 158 CHCl3 + 89
nmide Et 2 O
rortolmethylraorpholine . oil 89
Aenlyleodcimethylmorpholine . 118-120 89
ehloroplatinate . . . . 177 89
BIBLIOGRAPHY TO C H A P T E R VI
J. B E N T L E Y , ROBINSON, and WAIN, 33. H O F F M A N N - L A ROOHE AND C O . , D.
J.C.S., 1952, 958. R.-P. 286,743 (1914); Frdl. 12, 741.
2. H o w , Ann., 1853, 88, 336. 34. VON BBATTN, Ber., 1914, 4 7 , 2312.
3. GRIMATJX, Ann. CUm. Phys., 1882 (5), 35. PSCHOBB and DICKHATTSEB, ibid.,
27, 273. 1912, 4 5 , 1570.
4. Compt. Rend., 1881, 93, 591. 36. EARBENFAB. VOBM. F . B A Y E R AND
5. H E S S E , Ann., 1883, 2 2 2 , 203. Co., D. R.-P. 233,325 (1910); Frdl.
0. VONGERICHTEN, Ber., 1897, 30, 354. 10, 1218.
7. PSCHOBB, R O T H , and TANNHATTSER, 37. PSCHOBB, Ber., 1906, 39, 3130.
ibid., 1906, 39, 19. 38. and DICKHATTSEK, ibid., 1911,44,
8. K N O B B a n d SMILES, ibid., 1902, 3 5 , 2633.
3009. 39. R E I D E L A K T . - G E S . , D. R.-P. 261,588
9. BENTLEY, Unpublished results. (1910); Frdl. 11, 989.
10. ROBINSON, Proc. Roy. Soc., 1947. 40. RAPOPORT, J. Org. Ohem., 1948, 13,
11. Nature, 1947, 160, 815. 714.
12. VAN DTTIN, ROBINSON, and SMITH, 41. PSCHOBB and DICKHAUSEB, Ber.,
J.O.8., 1926, 903. 1912, 4 5 , 1567.
13. SMALL, J. Org. Ghem., 1947, 12, 359. 42. K N O B B and Rom, ibid., 1911, 4 4 ,
H . K N O B B , Ber., 1894,27, 1144. 2754.
15. SOHBYVER a n d L E E S , J.O.B., 1901, 43. P A L T I S and H E C Z K O , Monatsh., 1922,
563. 43, 255.
10. K N O B B and H A W T H O B N E , Ber., 1902, 44. VONGERICHTEN, Ann., 1897, 279, 204.
35, 3010. 45. SMALL a n d TUBNBTJLL, J.A.G.S., 1937,
17. and HOBLEIN, ibid., 1906, 39, 59, 1541.
4412. 46. VONGERICHTEN a n d H H B N E R , Ber.,
18. O P P E , ibid., 1908, 4 1 , 975. 1907, 40, 2827.
19. K N O R R , H O B L E I N , a n d GBIMME, ibid., 47. a n d D E N S D O B I T , ibid., 1907, 4 0 ,
1907, 40, 3844. 4146.
20. BUTLER, and HOBLEIN, Ann., 48. PSCHOBB, ibid., 1912, 4 5 , 2212.
1909, 368, 305. 49. VONGEBICHTEN, ibid., 1899, 32, 1047.
21. EiscHEK and VONGBBICHTEN, Ber., 50. VON B B A U N a n d CAHN, Ann., 1927,
1886, 19, 792. 451, 55.
22. K N O B B , ibid., 1899, 22, 181. 51. MOSETTIG, J. Org. Ohem., 1940, 5, 4 0 1 .
23. i b i d . 1113. 52. B E N T L E Y a n d W A I N , J.O.S., 1952, 972.
24. ibid., 1904, 37, 3494. 53. F A L T I S and STJTPAN, Pharm. Monatsh.,
25. ibid. 3499. 1923,4, 189.
20. ibid. 3507. 54. FEETJND, M E L B E B , and SCHLESINGEB,
27. VONGEBICHTEN a n d SOHBOTTBB, ibid., J. pr. Ohem., 1920, 101, 1.
1882, 15, 1484. 55. S P E Y E K and K B A U S S , Ann., 1923,
28. ibid., 1896,29, 65. 432, 233.
29. ibid., 1901, 34, 2722. 56. W I E L A N D a n d KOBALECK, ibid., 4 3 3 ,
30. MOSETTIG and MEITZNER, J.A.C.S., 267.
1934, 56, 2738. 57. K N O L L AND C O . , D. R.-P. 365,683
81. Q ULLAN a n d ROBINSON, J.O.S., (192I);.FMi!i!. 14, 1301.
1023, 080. (58. D. R.-P. 380,010 (1922); Vrdl. 14,
82. VoNGiimiaiLTnw, Ber., 1807,30, 2439. 1302.
OH. v i T H E CODEIMETHINES ANDTHEIR DERIVATIVES 123
59. KNOLL AND CO., Arch. Pharm., 1923, 75. CAHN, J.O.8., 1926, 2562.
261, 140. 76. VONGEBIOHTEN, and MITLLEB, Ber.,
60. D. R.-P. 607,931 (1934); Frdl. 21, 1903, 36, 1590.
652. 77. SMALL and PALMER, J.A.G.8., 1939,
61. D. R.-P. 617,238 (1934); Frdl. 22, 61, 2186.
583. 78. VON B R A O T , Bur., 1914,47, 2312.
62. D. R.-P. 623,821 (1934); Frdl. 22, 79. K N O B E , HOELETN, and STAUBAOH,
584. ibid., 1909, 42, 3511.
63. S P E Y E R and KOTTLEN, Ann., 1924, 80. SMALL a n d MALLONEB, J. Org. Chem.,
438, 34. 1947, 12, 558.
64. W I E L A N D a n d K O T A K E , ibid., 1925, 81. A C H a n d K N O B B , Ber., 1903, 36, 3067.
444, 69. 82. K N O B E a n d SOHNBIDEB, ibid., 1906,
65. LTTTZ and S M A L L , J.A.G.S., 1932, 54, 39, 1414.
4715. 83. and HOBLEIN, ibid. 3252.
66. ibid., 1934, 56, 1741. 84. ibid., 1907, 40, 2042.
67. ibid., 1935, 57, 361. 85. PSOHOBB a n d E I N B E O K , ibid. 1980.
68. ibid., 1934, 56, 2466. 86. HOLMES a n d L E E , J.A.G.S., 1947, 69,
69. F I N D L A Y and S M A L L , ibid., 1950, 72, 1996.
3249. 87. S P E Y E B and K O U L E N , Ber., 1931, 6 4 ,
70. SMALL and RABOPOBT, J. Org. Chem., 2815.
1947, 12, 284. 88. VONGEBIOHTEN, ibid., 1899,32, 2379.
71. PSOHOBB and DICKHAUSEE, Ann., 89. VON BBATTN, ibid., 1919, 52, 1999.
1910, 373, 80. 90. CASTELLIZ a n d H A L L A , Z. Krist., 1943,
72. Ber., 1912,45, 1570. 105, 156.
73. and ROLLETT, Ann., 1910,373, 1. 91. VON KLOBtnEOW, Z. phys. Chem.,
74. ibid. 15. 1899, 3 , 476.
VII
NEOPINE
N K OPiNE was first isolated by Dobbie and Lauder from the last mother
liquors from the processing of the opium alkaloids after all other bases
had been eliminated [I]. This remains the only source of the base.
Tlie method of isolation has since been improved and the alkaloid can
bo separated from codeine through the sulphates [2]. The base was first
allotted the formula C 18 H 2 IO 1 N and the name 'hydroxycodeine'; it was
nhown to contain one OMe, one NMe, and t o be a tertiary base. I t s
colour reactions and ultra-violet absorption spectrum are practically
identical with those of codeine [I].
Neopine was later shown to have the composition C18H21O3N, isomeric
with codeine [3]. I t contains a hydroxyl group, as is evinced by the
preparation of an acetyl ester, and on hydrogenation it affords dihydro-
codeine, so t h a t it can only differ from codeine in the position of the
alicyclic double bond. The nature of the isomerism was elucidated by
exhaustive methylation. Codeine [i] methiodide gives a-codeimethine
[n] on degradation, and the latter can be isomerized t o /3-codeimethine
[HI], with migration of the 7:8 double bond into the 8:14-position,
under the influence of alcoholic potassium hydroxide. Neopine methio-
dide degrades directly to /J-codeimethine [in] and therefore neopine
must have the structure [iv] with the double bond already in the 8:14-
position [3]. The sodium-liquid ammonia reduction of neopine methio-
dide yields a-dihydrocodeimethine-B (neopine dihydromethine) [v] [4],
identical with the product of sodium-alcohol reduction of a- and /3-
codeimethines (see Chap. VI).
Movement of the double bond does not occur during the methylation
of morphine to codeine, from which reaction no neopine can be isolated
[2]. Unlike codeine neopine can be demethylated b y hydrobromic acid
and glacial acetic acid, the product being 6-acetylneomorphine [vi],
probably formed by way of the 3:4-diacetyl derivative, which readily
loses the 3-acetyl group in dilute acetic acid. Demethylation with 48
per cent, hydrobromic acid alone affords neomorphine [vn], also ob-
tained by the hydrolysis of [vi], b u t the free dihydroxy-compound is
readily soluble in water and difficult to isolate. Neomorphine is con-
verted to neopine b y diazomethane. Reduction of 6-acetylneomorphine
yields 6-acetyldihydromorphine, which can be hydrolysed to dihydro-
morphine [6].
MeCX HO MeO
B I B L I O G R A P H Y TO C H A P T E R V I I
1. D O B B I B a n d LAITDEB, J.O.S., 1911, 34. 5. ROBINSON and SALTER, Unpublished
2. HOMEYKB a n d SHILLING, J- Org. Chew,., results.
1947, 12, 356. 6. SMALL, J. Org. OUm., 1947, 12, 359.
IS. VAN D U I N , KOBINSON, and SMITH, 7. BniNTLEY, Unpublished results.
.I.O.S., 11)20, 90!!. 8. RATOPOBT and BONNICK, J.A.O.S.,
4. IiU)MTUUY a n d W A I N , ibid., J052, 072. 1001, 7 3 , 2872.
VIII
THE HALOGENOCODIDES AND
HAL0GEN0M0RPHIDES
C O D E I N E [I, R = Me] and morphine [i, R = H] contain an alcoholic
hydroxyl group and can form 'esters' of halogen hydracids in which
this group is replaced by a halogen atom. Theoretically there are four
possible isomers of each halogen derivative as the hydroxyl group is
located on an asymmetric carbon atom and Walden inversion is possible
during the replacement reaction, and moreover allylic rearrangement is
possible, giving rise to 8-substituted derivatives analogous to ip- and
allo-)/r-codeine [n, R = Me] and /?- and y-isomorphine [n, R = H ] . Of
those possible isomers two only are known in the chloro-series and one
in the bromo- and iodo-series.
STRUCTURE
a-Chlorocodide has been conclusively proved to have the structure
[iv] with the chlorine atom at C-6, as it can be reduced without elimina-
tion of the halogen to 6-chlorodihydrocodide [v], identical with the
product of interaction of dihydrocodeine [vi] and phosphorus penta-
chloride [20], during which there is no possibility of migration of the
substituent to C-8 [19]. This structure is in harmony with all the pro-
perties of a-chlorocodide provided allowance is made for allylio re-
arrangement during replacement of the halogen. There is no evidence
to show whether [iv] belongs to the codeine or isocodeine series, as
Walden inversion is possible during the production of [iv] and [v] from
the corresponding alcohols, or in the hydrolysis of a-chlorocodide to
isocodeine (see below).
REDUCTION
The system OCHCHCl in a-chlorocodide and a-chloro-
1 2 3 4
morphide bears a certain resemblance to the system OCHCH=C
in dosoxyoodeino-C [vn] and ^-eodoino [n, R = M!o] in that both are
128 H A L O G E N O C O D I D E S AND H A L O G E N O M O R P H I D E S CH. VIII
absorbed all the product is soluble in water as a halide salt [23]. The
reduction of bromocodide is similar to the above. The maximum
amount of tetrahydrodesoxycodeine [vin] produced in reductions (b),
(c), and (d) is only 5 per cent.in marked contrast to the hydrogenation
of/?-chloroeodide (q.v.) when large amounts of [vin] are formed.
. Me0 MeO
T ^J l ^ EtM8I
Zn/e.tOH^ HO HO
O I I ELECTROLYTjC Na/EtOfl
/NMe f I T /NMe
Cl^v^ Nd/EtOH
HYDROLYSIS
The hydrolysis of a-chlorocodide with water at 140-150 C. was first
thought to give codeine [7-8, 35], b u t subsequent investigations have
shown t h a t though the other three isomers of codeine can be obtained
by the hydrolysis of halogenocodides, in no case is codeine formed.
Similarly the hydrolysis of the halogenomorphides affords no morphine.
The first product of hydrolysis of a-chlorocodide to be clearly recog-
nized was ^-codeine [n, R = Me] [36], and following the isolation of
isocodeine [18, 37] and allo-^-codeine [18] from the hydrolysis of
bromocodide (q.v.) all three isomers were obtained b y the hydrolysis
of a- and /3-chlorocodide with acetic acid, the proportions varying with
the two isomeric chloro compounds t h u s :
a-chlorocodide -> 25% isocodeine-f-45% ^-codeine+15% allo-^-codeine [38],
j8-ehlorocodide -> 35% isocodeine-f-10% i/r-codeine+20% allo-^-codeine [38].
The production of all three isomers has been confirmed [10]. Iodocodide
also yields all three isomers of codeine on hydrolysis [39], but only iso-
and allo-i/(-codeine appear to have been isolated from the hydrolysis of
bromocodide [14, 16, 18, 37].
The hydrolysis of a-chloromorphide follows a similar pattern, a- [18,
40], j3- [18, 40-41], and y-isomorphine [18, 40, 42] being formed. Bromo-
morphide gives all three isomers [18].
Attempts to hydrolyse 6-chlorodihydrocodide have failed [10].
As shown in Chapter IV, codeine and isocodeine are known to have a
hydroxyl group at C-6 by oxidation to codeinone [xiv] followed by
degradation to 3:4:6-trimethoxyphenanthrene [xv], whereas ip- and
CH 3 -CH,
Cl ' \ ^ ^CH 3 H" " ^ ^OH
R E P L A C E M E N T OE H A L O G E N B Y G R O U P S OTHEB. T H A N
HYDROXYL
Replacement of the halogen atom of a-chlorocodide and cu-chloro-
morphide by groups other than hydroxyl always involves migration of
tho substituent, which appears at C-8 in the final product. This is
demonstrated by the results of hydrogenation of the products, for
compounds having a 6:7 double bond conjugated with the cyclic ether
group readily suffer scission of the latter during hydrogenation, with
tho production of phenolic tetrahydro-derivatives.
(a) i/r-Codeine methyl ether [XXVII, R OMe] is formed on heating
re-ohlorooodido with sodium mothoxide at 100 C. [49-52]. On catalytic
hydrogouation it gives totrahydro-i/r-codoino motliyl other [XXVJII,
CH. VIIi a-CHLOROCODIDE AND ct-CHLOEOMORPHIDE 133
MBTHINE BASES
a-Chlorocodeimethine [xxxrv] can be obtained by the action of
phosphorus trichloride on a-codeimethine [xxxv] in chloroform (if no
solvent is used only the phosphorous ester of [xxxv] is obtained) [65],
but not by the degradation of a-chlorocodide methohydroxide. The
latter is a strong base whose solution contains no chloride ions, but on
boiling the solution becomes neutral and gives a copious precipitate
with silver nitrate [66]. With phosphorus pentachloride [xxxv] gives
a dichlorocodeimethine in which the additional chlorine atom is in
either position 9 or 10 as acetolysis of the base gives 3-methoxy-4:9
(or 10)-diacetoxyphenanthrene [65] (see Chap. VI).
I n the same way that hydrolysis of a-chlorocodide gives a mixture of
isomers of codeine but no codeine, so hydrolysis of a-chlorocodeimethine
gives a mixture of y-, -, and e-codeimethines but no a-codeimethine
[67]. y-Codeimethine also gives a-chlorocodeimethine on treatment
with phosphorus pentachloride [68].
Catalytio hydrogenation of a-chlorocodeimethine gives a mixture of
a crystalline 'dosoxytetrahydrooodeimethine' (dihydrodesoxycodeine-
D Dihydromothine) [xxxvi] that oan be degraded to a nitrogen-free
OH. VIiI a-CHLOROCODIDE AND <x-CHL0R0M0RPHIDE 135
product Ci7H20O2, and an oily isomer of [xxxvi] that resists degrada-
tion [68].
, 8 - C H L 0 R 0 C 0 D I D E AND tf-CHLORQMORPHIDE
PREPARATION
^3-Chlorocodide is formed by the isomerization of a-chlorocodide by
heating alone above its melting-point [56] or with concentrated hydro-
chloric acid at 60-70 C. in sealed vessels [69] and also in the last-
montionod manner directly from i/<-codeine or codeine, presumably
through the a-isomor [69], though it is formed directly in 10-15 per
cent, yiold during tho interaction of codeine and thionyl chloride [19].
OonsidorabJo decomposition occurs whon a-ohlorooodide is heated alone,
13G HALOGENOCODIDBS AND HALOGENOMOKPHIDES CH. VIII
STRUCTURE
/3-Chlorocodide is believed to have the structure [XLI] and to be formed
from the a-isomer by an a.: y shift of the halogen, as on catalytic reduc-
tion it behaves as if i t contained the system OOHC=C, always
giving considerable quantities of phenolic products as does ^-codeine
[n, R = Me]. However, [XLI] has not been definitely proved to be the
structure as /?-chlorodihydrocodide, which can be prepared in low yield
by the hydrogenation of /?-chlorocodide, is not identical with 8-chlorodi-
hydrocodide [XLII] prepared b y the treatment of both dihydro-^-co-
deine-A [XLIII] and its epimer dihydroallo-i/r-codeine-A with phosphorus
pentachloride [19]. The configurations epimeric with 6- and 8-chlorodi-
hydrocodides remain possible for /3-chlorodihydrocodide. Attempts to
chlorinate dihydroisocodeine with phosphorus pentachloride give only
phosphorus-containing products, while thionyl chloride chlorinates the
dihydrocodeine isomers in the benzene ring only, sodium and alcohol
reduction converting the products back to the starting materials [19].
REDUCTION
(a) Hydrogonation of /3-chlorocodide hydrochloride in alcoholic
liydrogon ohloridc using a platinum oxide catalyst affords a small
quantity of /3-oh!orodihydrooodide together with tetrahydrodesoxy-
OH. VIIi /3-CHL0R0C0DIDE AND jg-CHLOROMOEPHIDB 137
codeine [vin] [19]. (Speyer and Krauss obtained the latter by the
reduction of allo-i/<-chlorocodide [7O].)
(b) Reduction of/3-chlorocodide in dilute acetic acid with a colloidal
palladium catalyst gives mainly dihydrodesoxycodeine-D [ix] but also a
considerable amount of tetrahydrodesoxycodeine [vin] [30, 34]. The
former is presumably formed by initial 1:4-reduction of the system
1 2 3 4
C=CCCl and the latter by 1:6- or 1:4-reduction of the system
1 2 3 4 5 6
0CC=C-C-Cl.
(c) Hydrogenation of /6-chlorocodide in neutral solution with a
palladized barium sulphate catalyst gives substantially the same results
as (6), the product consisting of 70 per cent. dihydrodesoxycodeine-D
and 30 per cent, tetrahydrodesoxycodeine [23], whilst /3-chloromorphide
under these conditions is converted almost exclusively to dihydro-
desoxymorphine-D [15].
(d) 100 per cent, tetrahydrodesoxycodeine is formed by hydrogena-
tion of /3-chlorocodide in neutral solution with a platinum oxide
catalyst [23]. No trace of a dimolecular compound could be detected
in reductions of /3-chlorocodide. The effect on the hydrogenation in
going from the base in neutral solution to the salt in acid solution is less
marked with the morphides than with the codides, and weakly acid solu-
tions increase the amount of tetrahydrodesoxymorphine obtained [15].
(e) Desoxycodeine-A [xi] results from the zinc-dust and alcohol
reduction of /3-chlorocodide, which in this way resembles the a-isomer;
the reduction must proceed by 1:6-addition of hydrogen to the system
1 2 3 4 5 6
OCC=CCCl. [xi] does not, however, result from the treat-
ment of /3-chlorocodide with Grignard reagents, when no reaction occurs
[27]; this is no doubt due to the fact that iodocodide is a necessary
intermediate in the production of [xi] in this way, and /3-chlorocodide
cannot be converted to an iodocompound [19, 27].
(/) Electrolytic reduction of /?-chlorocodide also gives desoxycodeine-
A [22, 27].
HYDROLYSIS
/3-Chlorocodide gives the same products as does the a-isomer on
hydrolysis,_namely, isocodeine [10, 38, 69], (/(-codeine [10, 38], and
allo-i/f-codeine [10, 38, 69], but the proportions (55 per cent., 10 per
cent., and 20 per cent, respectively) differ from those obtained from
a-chlorocodide (25 per cent., 45 per cent., and 15 per cent.) [38].
R E P L A C E M E N T OF H A L O G E N B Y G R O U P S O T H E R THAN
HYDROXYL
Tho replacement of the halogen of the/J-chlorocodides and morphides
roHulta in derivatives having tho new substituont at C-O, and if an
138 HALOGENOCODIDES AND HALOGENOMORPHIDES OH. VIII
J S - C H L O E O M O B P H I M A N D T H E M O R P H I N E -> A P O M O R P H I N E
CONVERSION
I n warm concentrated hydrochloric acid morphine [XLIV] adds one
mole of hydrogen chloride at the 4:5 oxygen bridge and suffers re-
placement of the alcoholic hydroxyl group by chlorine, coupled with an
a: y-shift of the latter as in the production of /3-chloromorphide, the
product being dichlorodihydrodesoxymorphine [XLVI] hydrochloride.
This readily suffers loss of hydrogen chloride and closure of the oxygen
bridge to give /3-chloromorphide [XLV] even in boiling water. The ease
of this bridge-closure is remarkable in view of the unreactivity of the
4-hydroxyl group to diazomethane, which converts [XLVI] only to a
monomethyl ether that can be converted to jS-chlorocodide by sodium
bicarbonate. /3-Chloromorphido is an intermediate in the production of
[XLVi] from morphine, as is shown by the fact that if tho reaction between
morphine and hyclroohlorio aoid is arrested at tho point at which
OH. Yin (3-CHLOROCODIDE AND 0 - C H L O R O M O R P H I D E 139
NMe
HO H0V
HO
[XLIX] [XLVIII]
NMe
8-CHLORODIHYDK,OCODIDE [XLII]
This base is formed together with a small quantity of 1:8-dichloro-
dihydrocodide by the action of phosphorus pentachloride on dihydro-i/r-
codeine-A [XLIII] and its epimer dihydroallo-i/t-codeine-A. I t is an
exceptionally stable substance, being unaffected by electrolytic or
sodium and alcohol reduction; heating with sodium methoxide under
pressure simply causes demethylation to 8-chlorodihydromorphide [19],
but prolonged boiling with sodium in c?/cfohexanol causes loss of hydro-
genchloride and production of desoxycodeine-D [LII, R = Me] and a
small amount of the demethylated substance, desoxymorphine-D
[LII, R = H] [19, 80].
^-Chlorocodide, obtained together with a-chlorocodide by the treat-
ment of i/r-codeine with phosphorus pentachloride [12] is most probably
identical with the a-isomer [1O].
Allo-i/f-chlorocodide, reported to result from the interaction of
phosphorus pentachloride and allo-i/r-codeine [70], was subsequently
shown to be |8-chlorocodide [10].
Tetrahydro-i/f-chlorocodide was prepared by the action of phos-
phorus pentachloride on tetrahydro-^-codeine [LIII] and reported to be
reduced by sodium and alcohol to a tetrahydrodesoxycodeine [70],
the properties of which are so inadequately described as to preclude the
establishment of its identity.
STRUCTURE
Bromocodide and bromomorphide are believed to have structures
analogous to those of the y8-chloro-compounds, which they resemble in
many of thoir reactions. Replacement of the halogen atom by other
gt,'ou])H gives riso in all OOBOH to O-Bubstitutod compounds. However, the
OH. VIiI BR0M0C0DIDE AND B R O M O M O R P H I D E 141
reduction of these bases more closely resembles the reduction of the
a-chloro-compounds t h a n the reduction of the /3-chloro ones. More-
over, bromo- and a-chlorocodides can be converted to iodocodide,
whereas the /3-chloro-compound cannot, though this is unreliable
evidence on which to base a structural theory, as bromo-compounds
are generally more reactive t h a n their chloro-analogues. Bromocodide
has not been reduced to a bromodihydrocodide.
REDUCTION
In all reductions of bromocodide the bromine atom is eliminated.
(a) Hydrogenation of bromocodide over palladized barium sulphate
in neutral solution gives 94 per cent. dihydrodesoxycodeine-D [ix] [23].
(b) Hydrogenation using a palladized calcium carbonate catalyst in
neutral solution gives 94 per cent, amorphous base, which is obtained
in 100 per cent, yield using platinum oxide as catalyst. I t is bis-6:6'-
dihydrodesoxycodeine-D [x], identical with the product obtained from
a-chlorocodide [23].
(c) Reduction of bromomorphide in neutral solution over palladized
barium sulphate gives a small amount of dihydrodesoxymorphine-D
and 70 per cent, of an undistillable oil, probably bis-6:6'-dihydrodesoxy-
morphine-D [15].
(d) Electrolytic reduction of bromomorphide gives desoxymorphine-
A [15].
(e) Bromomorphide is converted to /3-isomorphine (by hydrolysis)
and desoxymorphine-A by reduction with amalgamated zinc and 6 N.
hydrochloric acid [15].
HYDROLYSIS
Hydrolysis of bromocodide affords a mixture of isocodeine [16, 37]
and alio-i/r-codeine [17, 37, 69], which readily form a molecular com-
pound, m.p. 145-145-5 C , [a]^1 = 205 [17, 37, 69]. Neither codeine
nor i/t-codeine have been isolated from this hydrolysis. Bromomorphine
furnishes a mixture of a- [14, 18], /?- [14, 18], and y-isomorphine [18].
M I S C E L L A N E O U S R E A C T I O N S OF THE H A L O G E N O C O D I D E S
(a) 6-Chlorodihydrocodide yields an N-oxide on heating with hydro-
gen peroxide in acetic acid [20], and this can be sulphonated to 6-
chlorodihydrocodide-N-oxide sulphonic acid and nitrated [90]. Both
the N-oxide and its sulphonic acid are reduced to the base by sulphurous
acid [20, 90].
(6) a,- and /3-Chlorooodide suffer the expected replacement of the
N-Mo group by N-ON on treatment with oyanogen bromide, giving
CH. VIII IODOCODIDE AND I O D O M O R P H I D E 143
H
MeOOC CHO 0C
/NMe
/NMe
MeOO MeO
-NMe /NMe
Solvent
for Specific
Compound m.p. "G. recrystn. form rotation Temp. Solvent
a-chlorocodide 151-153 prisms -383 26 CHCl8
hydrochloride . syrup
acid sulphate -2H2O 192-193 H2O -1OM 20 H2O
acid tartrate 198-200 H2O needles -219-3 27-5 H2O
methiodide 168 -215 15
y3-chloroeodide 152-153 EtOH or plates -10 15 EtOH
Bt 2 O
hydrochloride . 168-171 BtOH -3-9 30 MeOH
hydriodide H2O needles 0 26 H2O
acid tartrate 190-192 H2O + 8-3 20 H2O
methiodide indefinite MeOH + 4-6 15 20%
MeOH
a: /3-chlorocodide molecular compd. 115-117 EtOH -150-4 25 EtOH
1-chloro-a-chlorocodide .
Bichlorocodide 196-197 EtOH prisms
hydrochloride . D.160-170
1-bromo-a-chlorocodide . 131 ligroin prisms
a-chloromorphide . 193 MeOH -375-2 MeOH
hydrochloride . EtOH -315-3 20 H2O
hydrobromide . EtOH 19 H2O
methiodide 207 MeOH prisms
Acetyl-a-chloromorphide. 174-178 EtOH
hydrochloride needles
/3-chloromorphide . 188 Et 2 O prisms 15 MeOH
nitrate cryst.
methiodide 210d. H2O
Acetyl-/3-chloromorphidc 163 EtOH needles
hydrochloride . cryst.
methiodide 177
Trichloromorphide c. 1953. EtOAc -285 21 MeOH
hydrochloride . H2O -245-6 20 H2O
Trichlorocodide 143-143-5 EtOH -302 25 BtOAc
hydrochloride . H2O 25 H2O
I 146* -218
6-chlorodihydrocodide 172-5- EtOH 27 CHCl1
l 174 -177-8
hydrochloride . 203-204 26 H2O
then 225 -129-5
^-tartrate . 191-192
f 253*
methiodide I 244 needles
H-oxide 214 H2O
6-clilorodihydroeodide mothine chlorodihydrocodeimcthlne-C (Chap. IV).
/3-chlorodihydrocodide c. 145 EtOH + 37-5 25 EtOH
8-chIorodihydocodide 123-124 75% -42-7 25 EtOH
acetone
tartrate 230-232
1:8-dichlorodihydrocodide 190-191-5 EtOH
Dihydrocodeine + S0Cla-5- 187-190
Dihydroisocodeine + SOCl2-S- 103-105
Dihydro-^-codeine-A+SOCl 2 - 108-112
(155 and
C-chlorodihydromorphide 233
1228-229 -145-0 30 EtOH
hydrochloride . 323-326 H2O -131-0 28 H2O
Hromocodide. . 162 BtOH plates + 56-5 20 EtOH
1-bromo-bromocodide 171-173 EtOH + 39 23 dioxanc
(169-170 + 65-9 25 MeOH
JBromomorpliide \> 200 MeOH + 73-9 28 MeOH
hydrochloride -H 2 O . H2O + 41-1 27 H2O
hydrobromide -H 3 O . 196 EtOH + 39-5 25
methiodide 200 needles
phenylcarbamate 204 needles
8-bromodihydrocodide . 230-232
O-bromodihydromorpliide ? 260-262
lodocodide . 159-100 MeOH needles + 136-5 22-5 CHCl2
or prisms
liydrooUlorldo -aiTl , 0 . 100-11)1 McOH + 127 23
180-182 n2o
hydriodldo
m.p. ol'nujmimltt with U^uUUmidlliydroaodhla derived from nliiomouluo series.
M47.1 L
146 H A L O G E N O C O D I D E S AND H A L O G E N O M O R P H I D E S OH. VIiI
Solvent
for Crystal Specific
0
Compound m.p. C. reerystn. form rotation Temp. Solvent Refs.
Iodocodide methiodide . 187-188 HaO needles 27
Iodomorphide . . . . vitreous + 123-2 27 MeOH 19
liydriodide . . . . H1O + + 114-5 25 H8O 19
atm. 00a
- acid tartrate . . . . 50% + 120-3 25 H8O 19
EtOH
benzoate . . . . . 159-160 EtOH + 115-5 26 EtOH 19
salicylate . . . . . 161 EtOH + 113-4 26 H8O 19
methiodide . . . . 50% + 90 2:6 50% 19
EtOH EtOH
a-chlorocyanonorcodide . 187-188 -390 20 CHOI, 91-92
/3-chlorocyanonorcodide . 197-198 -97-5 20 CHCl3 91-92
o-chlorocyanonormorphide D. 300 91
Chloroeodizone . . . . 104 ligroiD -231 22 EtOH 93-94
hydrochloride . . . . D. 213 needles 93
hydrobromide . . . . D. 201 93
-hydriodide . . . . D. 174 93
picrate . . . . . 171 93
Anhydrocodizone . . . . 110 yellow 93
needles
Chloroeodizone+KOAc-s- 189 93
Desoxycodizone . . . . 161 93
hydrochloride . . . . 223-224d. MeOH 93
ct-chloromorphinic acid . B. 192 MeOH plates 94
Methyl 6-desoxytetrahydromorphi- 200-205 plates 94
lactonate picrate
a-chlorocodinal . . . . 94
phenylhydrazone amorph. 94
Ozo-/3-chlorocodide oil 94
picrate . . . . . D. 217 HOAo needles 94
Ozo-6-chIorodihydrocodide [7:8-di-
hydrochlorocodizone] . 95
Chlorodihydrocodinal 206-207d. 96% plates 95
EtOH
perchlorate . . . . D. 270 prisms 05
Chlorodihydrodikonal perchlorate D. 206 95
6-chlorodihydrocodide-]sr-oxide sul- D. 290- 20
phonic acid 295
6-chlorodihydrocodide sulphonic acid D. c. 300 prisms 20
HNO 3 + 6-chlorodihydrocodide 223-224 EtOH yellow 20
crystals
' sulpho-/3-chIoromorphide' H8O HaO crystalline 71
6-methyl-O ?)-chlorocodide 162-5- Iigroin 63
163-5
6-aminocodide, acetyl deriv. . 117d. 86
6-carbamidoaminocodide 238-240 86
6-piperidocodide . . . . 75-80 subl. -233-9 25 MeOH 58
diperchlorate . . . . 172-175 H2O -113-4 23 H8O 58
6-piperidomorphide 216-217 EtOAc -234-8 23 MeOH 58
monomethiodide 236-241 H11O needles -145-8 23 50% 58
EtOH
Dihydro-6-piperidomorphide . 215-217 EtOAc -155-9 24 MeOH 58
8-aminocodide . . . . 128-5-129 Et 8 O -79-2 21 EtOH 58
dihydrochloride . . . . 300-305 95% -40-7 24 H8O 58
EtOH
Diacetyl-8-aminocodide . 218-22Od. EtOAc + 83-1 24 EtOH 58
Bihydro-8-aminocodide . amorph. -28-7 21 EtOH 58
d i h y d r o c h l o r i d e . . . . 274-277 97% -14-7 24 H8O 58
EtOH
Totrahydro-8-aminocodide 138-5-140 subl. -9-7 24 EtOH 58
dihydrochloride.... EtOH + 6-6 24 H8O 58
8-dlmethylaminocodide . 118 60
platinichloride . . . . 250 60
8-dlothylaminocodide 101-103 subl. + 42-6 23 MeOH 60, 58
dihydriodido . . . . 179-182 H8O + 22-9 26 EtOH 58
diporohlorato . . . . 180-183 H8O + 3-3 19 H8O 58
plaUulolilorldo . . . . D. 240 60
Totraliydro-H-dlotliylammocodldo . 154-157 subl. + 31-5 25 MeOH 68
monoptmililonito 234-238 11,0 + 18-3 20 H8O 58
8-<ll(>l.liyliimliLO()ynmmor(iodMu 187-188 1
--liliiMulnlilnrldii . . . . I). 2BO OL
H-tl 1 o(11 y In 1111u<111irji'i >111<I<i, 201 ZM HIlI)I. 1 (10-1 2L MoV)Il 11,58
CH. vizi HALOGENOCODIDES AND HALOGENOMORPHIDES 147
Solvent
for Crystal Specific
Compound m.p. "C. vecrystn. form rotation Temp. Solvent Refs.
8-diethylaminomorphide dihydrio-
dide-IiH 2 O . . . . 87-93 H2O + 2-6 25 H2O 58
diperchlorate . 114-116 H2O + 4-4 19 H2O 58
8-piperidocodide . . . . 116-117 subl. + 25-8 22 MeOH 33, 58
monohydriodide 234-237 H2O + 13-4 24 H2O 58
diperchlorate . . . . 181-183 HjO + 13-2 23 50% 58
EtOH
diacidsulphate . . . . 161-163-5 BtOH + 19-8 26 H2O 58
monomethiodide + 22-0 25 H2O 58
Dihydro-8-piperidocodide 167-169 BtOH -1-2 23 MeOH 58
Tetrahydro-8-pipcridocodide . c. 125 subl. + 36-7 25 MeOH 58
8-piperidomorphide 222-224 BtOH + 28-7 24 MeOH 58
dihydriodide . . . . 208-214 H2O + 14-9 23 H2O 58
monomethiodide 243-245 H2O + 23-7 23 50% 58
EtOH
Tetrahydro-8-piperidomorphide 270-280 + 45-1 26 10% 58
HOAc
Acetyltetrahydro-8-piperidomorphide 172-178 58
Dihydrohydroxychlorocodide . 213-5-214 BtOAc -151 22 10% 96
HOAc
l-chlorodihydrohydroxychlorocodide 163-5 BtOH prisma -141 22 10% 96
HOAc
Pentachlorooxycodide D. -289-8 25 acetone 19
Dichlorodihydrodesoxymorphine 230-235 + 276 27 50% 19
hydrochloride BtOH
B I B L I O G B A P H Y TO C H A P T E R V I I I
ANDEBSON, Trans. Boy. Soc Edin- 21. LTJTZ a n d SMALL, J.A.O.8., 1932, 5 4 ,
burgh, 1850, 20, 57. 4715.
Ann., 1851,77, 341. 22. SMALL a n d MOBHIS, ibid., 1933, 5 5 ,
MATTHIESSEN and W E I G H T , Proc. Boy. 2874.
Soc, 1869, 17, 455. 23. MOSETTIG, COHEN, and SMALL,
Ann. Suppl., 1870, 7, 170. J.A.C.S., 1932, 54, 793.
Proc. Boy. Soo., 1869, 17, 24. BITSCH a n d SCHMIDT, Ber., 1929, 6 2 ,
460. 2612.
- Ann. Suppl., 1870, 7, 177. 25. K N O B R a n d H O R L E I N , ibid., 1907, 4 0 ,
-Proc. Boy. Soc, 1869, 18, 376.
83. 26. and W A E N T I G , ibid. 3860.
Ann. Suppl., 1870, 7 , 364. 27. SMALL a n d COHEN, J.A.G.S., 1931,
9. VONGEBICHTEN, Ann., 1881, 210, 105. 5 3 , 2214.
10. S P E Y E B a n d R O S E O T E L D , Ber., 1925, 28. and LTJTZ, ibid., 1934, 56, 1738.
58, 1113. 29. CAHN, J.O.S., 1926, 2652.
11. WIBLAND and KAPBELMEIEE, Ann., 30. SMALL a n d COHEN, J.A.G.S., 1931,
1911, 382, 306. 5 3 , 2227.
12. K N O B B , B O T L E E , and H O E L E I N , ibid., 31. K N O L L AND CO., D. B.-P. 414,598
1909, 368, 305. (1922); Prdl. 11, 996; Houben, 4, 58.
13. W E I G H T , Cham. News, 1873, 2 7 , 287. 32. Jahresber. Chem. Tech., 1925, 7 1 ,
14. SOHBYVEB a n d L E E S , J.O.S., 1900, 123.
1024. 33. VONGEBICHTEN and MTJLLEB, Ber.,
15, SMALL, YXIEN, a n d E I L E E S , J.A.O.S., 1903, 36, 1590.
1933\55, 3863. 34. MANNICH a n d LOWENHEIM, Arch.
16. SOHBYVEB a n d L E E S , J.G.S., 1901, Pharm., 1920, 2 5 8 , 295.
563. 35. GOHLICH, ibid., 1893,231, 235.
17. LlCBS, Proc. Ohem. Soc, 1907, 23, 200. 36. K N O B B a n d H O B L E I N , Ber., 1906, 39,
18, -J.O.S., 1907, 1408. 4409.
19, SMALL, F A E I S , a n d MALLONEB, J. 37. L E E S a n d TTJTIN, Proc. Chem. Soc,
Org. Ohem., 1940, 5, 334. 1906, 22^ 253.
20, ITnWCWD, MBLTHOU, and ScHLHsnsraum, 38. K N O B R a n d HOKLHIN, Ber., 1908, 4 1 ,
J. pT. Ohem., 1020, 101, 1. 000.
148 HALOGENOCODIDES AND HALOGENOMORPHIDBS CH. ViH
39. a n d HAETMANN, ibid., 1912, 4 5 , 69. K N O B B and H O B L E I N , Ber., 1907, 4 0 ,
1350. 4883.
40. O P P E , ibid., 1908, 4 1 , 975. 70. S P E Y E E a n d K B A U S S , Ann., 1923,432,
41. L E E S , Proa. Chem. Soc, 1907, 2 3 , 200. 233.
42. K N O E B , H S B L E I N , a n d GEIMME, Ber., 71. A C H and STEINBOCK, Ber., 1907, 40,
1907, 40, 3844. 4281.
43. a n d HOBLEIN, ibid. 4889. 72. PSOHOBB and HOPPE, Ann., 1910,
44. ibid., 1903, 36, 3074. 373, 45.
45. a n d H O B L E I N , ibid., 1907, 40, 73. ibid., 15.
3341. 74. WABNAT, U.S. Pat. 2,087,134 (13 J u l y
46. ibid. 2032. 1937).
47. GTJIXAND and ROBINSON, J.C.S., 1923, 75. BOEHBINGEB-SOHN, Pharm. Zentral-
980. halle, 1910, 5 1 , 730.
48. Mem. Proc. Manchester Lit. 76. H O F F M A N N - L A ROCHE AND C O . ,
Phil. Soe., 1925, 69, 79. D. B.-P. 630,680 (1936); Frdl. 2 3 ,
49. K N O B B , D. B.-P. 224,347 (1910); 563.
Frdl. 10, 1222. 77. D. B.-P. 631,098 (1936); Frdl. 2 3 ,
50. a n d B O T H , Ber., 1911, 44, 2754. 564.
51. a n d HAETMANN, ibid., 1912, 4 5 , 78. Brit. Pat. 451,203.
1354. 79. Brit. Pat. 454,747.
52. PSCHOBR a n d DIOKHAUSEB, ibid. 1567. 80. SMALL a n d MALLONEE, J. Org. Chem.,
53. SMALL and LTJTZ, J.A.C.S., 1935, 57, 1940, 5, 350.
361. 81. W E I G H T , Pharm. J. Trans., 1871, 1,
54. TTJBNBULIi, a n d F I T C H , J. Org. 867.
Chem., 1938, 3 , 204. 82. Proa. Boy. Soc., 1871, 19, 371.
55. F A B I S a n d SHALL, ibid., 1936, 1, 194. 83. Pharm. J. Trans., 1871, 2 , 131.
56. PSOHOBB a n d R O L L E T T , Ann., 1910, 84. Chem. News, 1871, 2 3 , 133.
373, 1. 85. RAPOPOBT and P A Y N E , J. Org. Chem.,
57. M O E B I S and SMALL, J.A.C.S., 1934, 1950, 15, 1093.
56, 2159. 86. OCIIIAI and YOSIDA, J. Pharm. Soc.
58. SMALL a n d PALMER, ibid., 1939, 6 1 , Japan, 1939, 59, 425.
2186. 87. W E I G H T , Proc. Boy. Soc, 1871, 19,
59. W I E L A N D and K A P P E L M E I E B , Ann., 504.
1911,382, 306. 88. Pharm. J. Trans., 1871, 2 , 84.
60. VON B B A U N and K I N D L E B , Ber., 1916, 89. Chem. News, 1871, 2 3 , 302.
49, 2655. 90. S P E Y E E and W I E T E B S , Ber., 1921, 54,
61. FABBENFAB. VOBM. F . BAYEB AND Co., 2976.
D. B.-P. 222,920 (1909); Frdl. 10, 91. VON BBAUN, ibid., 1916,49, 750.
1217; Houben,3, 398. 92. H O F F M A N N - L A ROCHE AND C O . , D.
62. SMALL and TUBNBTTLL, J.A.G.S., 1937, B.-P. 286,743 (1914); Frdl. 12, 741.
59, 1541. 93. W I E L A N D and SMALL, Ann., 1928,
63. F I N D L A Y and S M A L L , ibid., 1950, 72, 467, 17.
3249. 94. S P E Y E E and R O E L L , Ber., 1930, 6 3 ,
64. SMALL a n d RAPOPORT, J. Org. Chem., 539.
1947, 12, 284. 95. ibid., 1929, 62, 209.
65. PSOHOBB, Ber., 1906, 39, 3130. 96. LTJTZ and SMALL, J. Org. Chem., 1939,
66. VONOKBICHTEN, Ann., 1897, 279, 204. 4, 220.
67. PSOHOBB and DIOKHATTSEB, Ber., 1912, 97. GOTO, Proc. Imp. Acad. (Tokyo), 1940,
45, 1570. 16, 403.
68. S P E Y E E and KOTJLEN, Ann., 1924, 98. and A E A I , Ann., 1941, 547, 194.
438, 34.
IX
THE DESOXYCODEINES AND T H E I R
DERIVATIVES
THE DESOXYCODEINES
T H E name desoxycodeine should logically be applied only to the sub-
stance of structure [i], in which the alcoholic oxygen of codeine [11]
has been eliminated; it is, however, also applied to two isomers of [i]
differing in the position of the double bond, and to a phenolic base [nr]
having an additional double bond in ring O.
D B S O X YCODEINB-A
Desoxycodeine-A [in] was first prepared by Knorr and Waentig [1]
(and called simply desoxycodeine) b y reducing a-chlorocodide [iv] with
zinc-dust and alcohol, a process t h a t must involve l:4-addition of
1 2 3 4
hydrogen to the system OCHCHCl of [iv]. I t may be pre-
pared in the same way from j8-chlorocodide [v, R = Cl] [1], bromocodide
[v, R = Br] [2], and iodocodide [v, R = I] [3]; by the interaction of
a-chlorocodide and methyl- or ethylmagnesium iodide, a reaction in
which the Grignard reagent functions solely in a reducing capacity and
in which iodocodide is very probably an intermediate [3]; and also b y
the electrolytic reduction of a-chlorocodide [3-4].
D E S O X Y C O D E I N B -B
Desoxycodeine-B, first thought to be a definite entity, was sub-
sequently shown to be anhydrous desoxycodeine-A containing a small
amount of a very persistent impurity. I t was obtained by the electro-
lytic reduction of a- and /3-chlorocodide [3-4]. Freund believed it to
be a dihydrodesoxycodeine and claimed it was formed in the electro-
lytic reduction of desoxycodeine-A and of 6-chlorodihydrocodide [4].
I n fact the two latter reactions yield isomeric dihydrodesoxycodeines [3].
Small and Cohen [3] showed t h a t 'desoxycodeine-B' is indeed a
desoxycodeine and t h a t on reduction it yields the same substances as
does desoxycodeine-A and accordingly suggested the structure [vin]
for it. However, Small and Morris [6], finding that electrolytic reduction
of a-chloromorphide gives desoxymorphine-A, which can be methylated
to desoxycodeine-A, re-examined desoxycodeine-B and discovered t h a t
it is identical with desoxycodeine-A.
DESOXYCODEINE-C
Desoxycodeine-C [ix] was the first of the non-phenolic desoxy-
codeines to be isolated. I t is obtained by heating 6-chlorodihydrocodide
[x] with sodium methoxide in methyl alcohol at 140 O. [3]; previously
no reaction had been observed at 120 C. [7]. Desoxycodeine-C was
presumably obtained by Knoll and Co. in this way, but was believed
to bo a dihydrodosoxycodeino [8-9]. I t is allotted the structure [ix] on
aooount oi'iho ouao with which phonolio substanoos are produced during
OH. I X THE DESOXYCODEINES 151
Br
[XXI] [XXII] [XXIII] [XXIV]
DESOXYCODEINE-D [DESOXYNEOPINE]
Dcsoxycodeine-D [xxv] was first prepared from 8-chlorodihydro-
oodide [xxvi] by prolonged boiling with sodium in cyclohexanol [13]
and subsequently from neopine [XXVII] by reduction of its ^-toluene-
sulphonyl estor with lithium aluminium hydride [17]. Degradation of
dosoxyoodeine-D affords desoxy-/3-codeimethino [xxvni] [13, 17], which
oaix also bo obtained by the isomorization of dosoxy-a-oodeimethino
OH. I X THE DESOXYCODEINES - 153
[xxix] (from desoxycodeine-E) [17]. Desoxycodeine-D also reacts with
cyanogen bromide as an allylamine, yielding an amorphous bromo-
compound that slowly loses bromine, indicating t h a t ring fission occurs
during the reaction [13]. Hydrogenation of desoxycodeine-D affords
dihydrodesoxycodeine-D [xni], and bromination gives the 1-bromo-
compound [13].
THE DIHYDRODESOXYCODEINES
Much inaccurate work b y Freund, Melber, and Schlesinger [4] led to
considerable confusion in the chemistry of the dihydrodesoxycodeines,
which was only rosolvod ton years later by Small and Cohen [21]. For a
154 T H E DESOXYCODEINBS AND T H E I R D E R I V A T I V E S OH. I X
DlHYDKODESOXYCODEINE-A
Dihydrodesoxycodeine-A was originally thought to be a definite
compound, but is now known to be a mixture of two bases. I t is
obtained by the sodium and alcohol reduction of desoxycodeino-A
[in], a-chlorocodide [iv] [1, 3, 10, 22], and desoxycodeine-C [ix] [3, 10],
and can be further reduced catalytically to tetrahydrodesoxycodeine
[xiv] [3]. I t was first stated to yield on degradation a methine base t h a t
absorbed two moles of hydrogen on reduction, giving tetrahydrodesoxy-
codeine dihydromethine (see below) [21], but later attempts to isolate
the methine base from the products of degradation were unsuccessful
[23].
Subsequently dihydrodesoxycodeine-A was proved to be a mixture
of dihydrodesoxycodeine-B [xv] (1 part) and dihydrodesoxycodeine-C
[xvi] (3 parts), isolated together as a result of the extraordinary ten-
dency of the salts of these two isomers to crystallize together.
This constant-proportion mixture is also obtained in small amount
by the sodium and alcohol reduction of the epimeric pair ^-codeine [24]
and allo-^-codeine [xi] [25], and of 8-ethylthiocodide [xxxin] [12].
Elimination of the group at C-8 presumably proceeds by 1:6-addition of
1 2 3 i 5 6
hydrogen to the system 0CHCH=CHCHR giving desoxy-
codeine-A [in] and the latter is then further reduced; 3:6-reduction
would give desoxycodeine-E and 5:6-reduction would involve an
activating effect of the double bond not found in codeine [24].
D l H Y D B O D B SO XYC OD BINE - B
I n addition to the production, mixed with dihydrodesoxycodeine-C
as described above, this dihydrodesoxycodeine-B [xv] can be obtained
by the electrolytic reduction of desoxycodeine-C [ix], the double bond
simply exerting an activating effect on the cyclic ether group in the
latter [3, 10, 21]. I t suffers no melting-point depression when mixed
with 'dihydrodesoxycodeine-A', a phenomenon frequently encountered
in this series [21-22]. On catalytic reduction it yields tetrahydrodesoxy-
codeine [21], and on degradation it gives dihydrodesoxycodeine-B
methine [xxxiv] [1O]. A compound that may be the dihydromethine
[xxxv] results from sodium and alcohol reduction of a-chlorotetra-
hydrocodeimethine [xxxvi] [22, 26], though this product may have the
isomeric structure [ x x x v n ] .
Two stereoisomers of dihydrodesoxycodeine-B methyl ether [ x x x v i n ]
have been prepared by the dehydration of the methyl ethers of dihydro-
thebainol [xxxix] and its C-14 epimer /3-dihydrothebainol, and a
racemic mixture of structure [xxxvin] prepared by an unambiguous
synthesis was shown b y comparison of infra-red spectra t o be identical
with the compound derived from the /?-series [27] (see Chap. X X V I I I ) .
DlHYDKODBSOXYCODBINE-C
Dihydrodesoxycodeine-C [xvi] results from the electrolytic reduction
of 6-chlorodihydrocodide [x] [3-4, 21], and, mixed with dihydrodesoxy-
codeine-B, as described under 'dihydrodesoxycodeine-A'. A substance
having'the propertios of dihydrodosoxycodeine-C is obtained by the
electrolytic reduction of 8-ethylthiooodido [ x x x m ] , but on degradation
156 T H E D E S O X Y C O D E I N E S AND T H E I B D E R I V A T I V E S OH. ix
this yields a methine base t h a t depresses the melting-point of dihydro-
desoxyoodeine-C methine [12].
Dihydrodesoxycodeine-C can be hydrogenated to tetrahydrodesoxy-
codeine [xiv] [21], and degraded to a methine base [XL] [1O]. A sub-
stance having the composition of dihydrodesoxycodeine-C dihydro-
methine [ x x x v n ] and the properties of a phenol is obtained by the
sodium-liquid ammonia-alcohol reduction of codeine methiodide [28].
This could arise by reductive scission of the nitrogen-containing ring
and 1:4 reduction of the allylic alcohol giving desoxycodeine-C dihydro-
methine [XLI], which would be expected to undergo further reduction
under such conditions to [xxxvn] or a mixture of [ x x x v n ] and [xxxv].
Codeine, however, is recovered unchanged from attempted reduction
with sodium, liquid ammonia, and alcohol [28].
DlHYDBODESOXYCODEINE-D
Dihydrodesoxycodeine-D [xin], the only non-phenolic dihydro-
desoxycodeine, can be prepared by the catalytic hydrogenation of
a-chlorocodide [rv] [29], /J-chlorocodide [v, R = Cl] [7, 29], bromocodide
[v, R = Br] [29], and desoxycodeine-C [ix] hydrochloride [6]. I t has
also been reported to be formed by catalytic reduction of codeinone
oxime [XLII] hydrochloride [30]. Dihydrodesoxycodeine-D methine
[XLIII] results from Hofmann degradation of the methiodide [7], and a
substance that is presumably the dihydromethine [XLIV] is obtained by
catalytic reduction of a-chlorocodeimethine [XLV] [26].
D l H YDEODBSOXYCODBINE-E
Dihydrodesoxycodeine-E is produced by the electrolytic reduction of
14-bromocodeinone [XLVII] [21, 32]; beyond the facts that it is phenolic,
can be reduced catalytically to tetrahydrodesoxycodeine, and can be
degraded to a methine base [32], nothing is known of its properties. I t
may have the structure [XLVIII].
TETRAHYDRODESOXYCODEINE
Only one tetrahydrodesoxycodeine has been prepared from thebaine,
though its antipode has been obtained from sinomenine. However, for
many years it was thought, as a result of the inaccurate work of
Freund [4], that two isomers, a- and /3-, existed, and it was required
t h a t any satisfactory formula for codeine be able to explain the iso-
merism. Freund accounted for the isomerism on the basis of the bridge
structure for codeine [XLIX], developed in connexion with phenyldi-
hydrothebaine, by postulating fission of the bridge in two ways to give
[L] and [LI] [4], and Gulland and Robinson suggested a similar explana-
tion based on [LII] [33], but later postulated stereoisomerism at C-14
when [LII] was modified to [n] [34].
T H E D E S O X Y M O R P H I N E S AND T H E I R
DERIVATIVES
The desoxymorphines bear the same relationship to morphine as the
desoxycodeines do to codeine and, though the series is less extensive,
each desoxymorphine can be methylated to the corresponding desoxy-
codeine.
D E S OX Y M O K P H I N B - A
Dosoxymorphine-A can be obtained by the electrolytic reduction of
a-chloromorphido |6] or bromomorphido [47] sand, together with /3-
iHomorpliino, by tlio reduction of thoso bases with amalgamated zino
160 T H E DBSOXYCODEIKTES AND T H E I R D E R I V A T I V E S cur. ix
and 6 N". hydrochloric acid [47]. Methylation of desoxymorphine-A with
diazomethane yields desoxycodeine-A [in] [6]. Hydrogenation of the
base affords tetrahydrodesoxymorphine [6].
DESOXYMORPHINE-C
This compound results from heating 6-chlorodihydromorphide with
sodium methoxide and methyl alcohol at 140 C. [6, 8-9] and, together
with dihydrodesoxymorphine-D, from the catalytic reduction of
dichlorodihydrodesoxymorphine [LX], obtained by the prolonged action
of concentrated hydrochloric acid on morphine at 50 C. [48-51, 52]. I t
gives desoxycodeine-C [ix] on methylation [6]. Catalytic reduction of
the base in glacial acetic acid over platinum oxide affords dihydrodesoxy-
morphine-D and tetrahydrodesoxymorphine [47], but only the latter
is formed on hydrogenation of an aqueous solution of the hydro-
chloride [6].
DESOXYMORPHINE-D
Desoxymorphine-D can be prepared by the demethylation of desoxy-
codeine-D [xxv] with pyridine hydrochloride at 215 C. [17], by the
action of phosphorus tribromide on dihydroallo-i/f-codeine [LXI] [13, 53],
and as a by-product in the preparation of desoxycodeine-D from
8-chlorodihydrocodide [13]. On methylation it gives desoxycodeine-D
[13, 17].
DESOXYMORPHINE-E
This results from the demethylation of desoxycodeine-E [xxx] [62].
A desoxymorphine was stated by Schryver and Lees [54] to result
from the reduction of a-chloromorphide with tin and hot concentrated
hydrochloric acid, but a repetition of this reaction afforded only small
amounts of material of different specific rotation that does not corre-
spond to any of the known desoxymorphines, and indeed it is doubtful
whether the morphine structure would survive such treatment, as even
in the a. > /J-chloromorphide conversion considerable amounts of
apomorphine [LXII] are formed. Wright also reported the production
of a desoxymorphine on heating bromocodide with hydrobromic acid
[55-58], but nothing further is known about this.
OH. ix T H E D E S O X Y M O R P H I N E S AND T H E I R D E R I V A T I V E S 161
D l H Y D B O D ES OX YMOBPHINB - D
Dihydrodesoxymorphine-D can be prepared by the bydrogenation
of the halogenomorphides in neutral or weakly acid solution [47, 59],
of desoxymorphine-0 in glacial acetic acid [47], and, with desoxy-
morphine-C, by reduction of the dichloro-compound [LX] [48-52].
The yield from bromomorphide is low, the main product being an
undistillable oil, probably bis-6:6'-dihydrodesoxymorphine-D [47].
Dihydrodesoxymorphine-D can be methylated to dihydrodesoxy-
codeine-D and the reverse change can also be accomplished [47]. Mild
oxidation of dihydrodesoxymorphine-D in alkaline solution affords
tetrahydrodidesoxypseudomorphine [60].
TETBAHYDBODESOXYMOBPHINB
This is formed by the demethylation of tetrahydrodesoxycodeine [6]
and by the hydrogenation of desoxymorphine-C [47], a-chloromorphide
[47], and /Msomorphine [LXIII] [61].
Solvent
for Crystal Specific
Compound m.p. "G. ncrystn. form rotation Temp. Solvent Befs.
Desoxycodeine-A-iH a O . 121-122 50% leaflets + 118-1 22 96% 3
MoOH EtOH
Desoxycodeine-A (anhyd.) 157 + 119-0 24 EtOH 6
/255-257 + 93-6 6
hydrochloride . . . . X c. 270 + 87-0 15 HjO 21
hydriodide . . . . 268-269 + 71-4 6
benzoate . . . . . c. 188 + 106-0 15 EtOH 1
salicylate . . . . . 220-5-221 + 104-4 6
methiodide . . . . 219-221 + 95-7 6
Acetyldesoxycodeine-A . oil 1
hydriodide . . . . 230 1
methiodide . . . . 270 1
Desoxycodeine-A methyl ether meth-
iodide . . . . . 251-252 + 108-0 15 EtOH 1
Desoxycodeine-A+Br,,-* 189-189-5 + 10-2 25 benzene 5
Desoxycodeine-A+HBr-> 149-151 -3-8 25 EtOH 5
Desoxycodeine-A methine 1
Desoxycodeine-A methyl ether
methine . . . . . oil 1
Desoxycodeine-B: Identical with desox ycodeine-.A
Desoxycodeine-C . . . . 105-106 ' EtOAc -199-4 20 95% 3
BtOH
hydrochloride-HjO . 114 EtOH -132-7 20-5 S1O 3
hydriodide-H 2 O 160-165 H0 prisms -131-6 19 95% 3
EtOH
salicylate . . . . . 195-196 EtOH -112-2 24 EtOH 11
methiodide . . . . 236-240 MeOH 3
Eacemate with antipode from sino-
menine series . . . . 85 15
methiodide . . . . 218 15
1-bromodeBOxyeodeine-C. 131-133-5 MeOH -288-5 26 EtOH 5
Cyanonordesoxycodeine-C 159-5-161 EtOH 13
O-methyldesoxycodeine-0 172-174 EtOH -242-0 20 EtOH 16
hydrochloride . . . . 262-263 Et,0 + -192-0 20 EtOH 16
EtOH
mothiodido . . . . 280-281 -149-0 20 BtOH 16
1 -ohloro-0-methykloBOxycodeine-C . 171-172 EtOH -226-0 20 BtOH 16
Dosoxycodolno-D . . . . 01-5-62 subl. -21-1 25 EtOH 17
/234-235 butanono -12-1 20 HaO 13
hydrochloride . . . . \288-230 + 5-9 H1O
25 17
aold nxalftto . . . . 225-22(1 MtOlI -10-9 25 H1O 17
aulil Uirlmto . . . . 804-8011 H11O 0 25 11,0 13
0147.1 M
162 THE D E S O X Y O O D E I N E S AND T H E I R D E R I V A T I V E S on. i x
Solvent
for Crystal Specific
Compound m.p. 0C. recrystn. form rotation Temp. Solvent
Desoxycodeine-D methiodide 283-234 MeOH + 16-1 25 MeOH
B-osoxycodeine-D methine (desoxy-/3- 75-76 H2O + plates + 314-0 25 dioxane
codeimethine) EtOH
perchlorate . . . . 230-231 EtOH + 182-5 25 acetone
picrate . 173-175d, EtOH + 91-5 25 acetone
methiodide . 314d. MeOH + 157-0 25 MeOH
1-bromodesoxycodeine-D 125-126 60% plates
BtOH
82-83 H2O + -68-0 25 MeOH
EtOH
Dosoxycodeine-E . H2O + BtOH
84 -58-9 20
EtOH
hydrochloride . 239-240 butanone -40-3 25 EtOH
perchlorate 25Od. H1O + -41-3 25 acetone
EtOH
acid tartrate 123-125 H2O -41-1 25 H2O
picrate 196-197
methiodide 257-258d MeOH -25-9 25 MeOH
Cyanonordesoxycodeine-E 149-150 H2O + -133-8 25 BtOH
EtOH
Desoxycodeine-E methine (desoxy-'
codeirnethine) oil + 130-0 25 dioxane
perchlorate 180-181 EtOH + 86-3 25 acetone
picrate 163-164 BtOH + 54-7 25 acetone
' c. 157 EtOAc -18-7 28
' Dihydrodesoxycodeine-A' is a mixture of dihydrodesoxycodeines-B and -C)
hydrochloride-BtOH . 158-160 BtOH -41-4 22 H2O
hydriodide 242-243 prisms
benzoate . 180
methiodide 250-251d. -7-5 20 EtOH
(170-173
Dihydrodesoxycodeine-B 128-131 H2O + t, -106-9 20 90%
BtOH EtOH
hydrochloride . 154-156d. BtOH -76-4 21 H2O
hydriodide 255-256 H2O -79-3 19 96%
EtOH
methiodide c. 175 H2O needles
Dihydrodesoxycodelne-B methyl
other oil
fumarate . 233-235
/J-dihydrodesoxycodeine-B methyl
other. oil
picrate 210-212
144-145-5 acetone ( -9-5 20 OHCU
Dihydrodesoxycodeine-B methine
X - 7 - 4 20 CHClJ
hydrochloride . cryst.
IMhydrodesoxy codeine-C. 109-111 H 2 O + + 5-6 24 BtOH
EtOH
hydrochloride . 241-243 EtOH + 11-2 27 H2O
hydriodide 242-243 H2O prisms + 8-2 24 H2O
methiodide 245-246 needles + 15-3 29 H2O
Kthylthlodihydrodesoxycodeine-C ? oil -59-8 24 EtOH
Dlhydrodcsoxyeodeine-C methine 175-176 -13-8 25 CHCl3
Wiliydrodesoxycodeine-0 dihydro
methine? . . . . 156-157 petrol plates
Diliydrodesoxycodeine-C (or -B)'
dlhydromethine(desoxytetrahydro-
a-codoimethine) . 163-164 Br
perchlorate 159
motliioiiide 248
methyl other hydriodide 170-171
methyl othor perchlorate 206-208
- nictliyl othor methiodide 210-212
Dlhydrodosoxyeodeino-D 106-107 Bt 2 O prisms -82-5 20 96%
BtOH
hyilrlodklo 250-251d. H2O needles
( 164- -29-0 18 HVO
nold tartrate 154-5
I 123-125 H1O .. -80-0 80
plm'ai.0 . . . . 207 H2O
2K(I
,.
prinmn
Illllt'lllolllllll iotoir
!ImiiiunllhytlroiUmoxyiioiltiliio-l) inn 157 MuO Il -ilV'O 2(1
UtOJl
CH. ix T H E D E S O X Y C O D E I N E S AND T H E I R DERIVATIVES 163
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form, rotation Temp. Solvent Refs.
1:6:7-tribromodihydrodesoxy- 184-5- -156-7 26 EtOH 5
codeine-D 185-5
Dihydrodesoxyeodeine-D methine . 86 Bt2O rhombs 7
hydrochloride-H2O 222 7
p i c r a t e . . . . . 154 7
methiodide . . . . 238 7
Dihydrodesoxycodeine-D dihydro-
methine (desoxytetrahydro-a-codei-
methine) . . . . . 156 EtOH 26
methiodide . . . . 235 26
isomeric b a s e . . . . oil 26
isomer hydriodide 208-210 26
isomer methiodide D.272-273 26
Bis-6:6'-dihydrodesoxycodoine-D amorph. -113-0 26 EtOH 29
monomethio&ide 246-25Od. needles -8-6 23 EtOH 29
dimethiodide . . . . 230-25Od. amorph. -71-5 28 4- 29
CH2OH
Dihydrodesoxycodeine-E 139-140 + 58-1 13 dil. 2 1 , 32
HOAc
salicylate . . . . 198 32
methiodide . . . . 199 32
Dihydrodesoxycodeine-E methyl
ether methiodide 245 32
Dihydrodesoxycodeine-E methine 32
hydriodide . . . . 220 32
methiodide . . . . 103 32
( 135* 41
() 123-124 petrol -72-3 18 benzene 23
Tetrahydrodesoxycodeine . { 1 -70-3 21 benzene 23
Ub) 157-158 J -33-6 24 95% 23
EtOH
I -32-0 20 95% 23
Tetrahydrodesoxycodeine JH2O EtOH
I -66-7 19 benzene 23
hydrochloride-EtOH . 260-262 EtOH+ prisms -23-5 20 H2O 4, 2 3
Et2O
hydriodide-H2O 245-246d. H2O needles -24-3 19 95% 4, 2 2 -
EtOH 23
f 235t 41
methiodide . . . . -33-3
1260-263 H2O 26 H2O 4,23
Bis-1: l'-tetrahydrodesoxycodeine . 230-238 (see also C h a p . X XV I ) 46
Tetrahydrodesoxycodeine methyl
ether oil 23
/164-1661 + 20-5t 14 H2O 40
hydriodide . . . . -21-8
1217-218 H2O needles 21 EtOH 23
methochloride . . . . 255-256 acetone -9-5 22 H2O 23
/257-258.T Et2O + 40
methiodide . . . .
(.256-257 EtOH -S-6 21 EtOH 4, 2 3
l 135 EtOH 4
1-bromotetrahydrodesoxycodeine 156- MeOH -28-2 26 EtOH 5
l 157-5
1-bromotetrahydrodesoxy-
codeine-HaO . . . . 119-128 acetone 5
Tetrahydrodesoxycodeine methine . 152-154 H2O + flakes + 66-2 24 MeOH 23
EtOH
Tetrahydrodesoxycodeine methyl
ether methine . . . . oil 4
hydriodide . . . . 175-185 4
methiodide . . . . 185-188 4
(156-157 10, 22
Tetrahydrodesoxycodeine dihydro- -14-5
148-150 H2O + needles 26 96% 23
mothine
EtOH EtOH
hydrochloride . . . . 251-252 H2O needles -82-1 26 96% 23
EtOH
- hydvlodido . . . . 219-220 H2O plates 22
porohlorato . . . . 150-153 H1O rods 22
ToU'iiliydrodosoxyoodelno rnothyl
olhcif dlliyilvomothtno . oil 22
liydrloilldo . . . . I7<1~ 170 11,0 22
tjernlilomdfl . . . . 11)4- K)Ii 11,0 22
--mntlilnilklo . . . . oil 22
* ttnmuuiln Willi (lornnollioxyilp o x y d l h y d r INlllUIIH'llll n. t RlIO(IlIlUt i. I AnUp UlI(I,
164 T H E D E S O X Y C O D E I N E S A N D T H E I R D E R I V A T I V E S OH. IX
Solvent
for Crystal Specific
Compound tn.p. C. recrystn. form rotation Temp. Solvent Refs.
Bromotetrahydrodesoxyeodeine from
tribromodihydrodesoxycodeine-D . 116-117-5 -3-3 25 BtOH 5
Isomer of tetrahydrodesoxycodeine
from above bromocompound 88-89 subl. needles 5
6-methyltetrahydrodesoxycodeine . 157-5- acetone -4-5 20 EtOH 16
158-5
hydrochloride . . . . 254-255 Et 2 O + + 8-0 20 EtOH 16
BtOH
acid oxalate . . . . 171-172 Et 2 O + + 4-8 20 EtOH 16
BtOH
methlodide . . . . 265-266 Et 2 O + + 6-4 20 EtOH 16
MeOH
Other alkyldi- and tetrahydrodesoxy-
codeines: see Chap. X I X .
Desoxymorphine-A 257-258 47
sulphate . . . . . 145-151 + 61-6 32 H2O 6
benzoate . . . . . 240-245 + 81-9 31 95% 6
BtOH
salicylate 248-250 EtOH + 93-6 25 MeOH 6
Desoxymorphine-C 189-190 BtOAc -155-7 31 95% 6
EtOH
hydrochloride IJH 2 O . uncertain 147-0 30 H,0 6
hydriodide . . . . 292-294 H2O -109-6 32 H,0 6
methiodide . . . . 260-264 85% -98-2 32 MeOH 6
BtOH
/260-261 EtOH -15-3 25 MeOH 17
Desoxymorphine-D 1254-255 EtOH 13
perchlorate . . . . 261-262 EtOH -23-5 25 H2O 17
Desoxymorphine-E 143-144 benzene -67-2 25 EtOH 62
Dihydrodesoxymorphine-D 188-189 BtOAc -76-8 28 MeOH 47
Dihydrodesoxymorphine-D JH 2 O 162-164 -78-6 28 BtOAc 47
hydrochloride . . . . 95% -68-6 27 H2O 47
BtOH
hydriodide . . . . H2O -48-4 25 H2O 47
sulphate . . . . . H2O -51-9 29 H2O 47
acid oxalate . . . . 50% -67-9 23 H2O 47
EtOH
salicylate . . . . 95% -42-8 28 BtOH 47
EtOH
methiodide . . . . EtOH -46-6 27 H2O 47
Bis-6:6'-dihydrodesoxymorphine-D ? oil 47
Dichlorodihydrodesoxymorphine: see
Chap. VIII
Tetrahydrodesoxymorphine /237-239 6
1172-184 EtOAc 47
hydriodide . . . . 268-271 H2O -32-7 24 H2O 6
methiodide . . . . 269-271 95% -31-4 31 MeOH 6
EtOH
BIBLIOGRAPHY TO CHAPTER IX
K N O K B a n d W A E N T I G , Ber., 1907, 4 0 , 9. K N O L L AND C O . , Jahresber. Chem.
3860. Tech., 1925, 7 1 , 123.
a n d HOKLEIN, ibid. 4883. 10. LTJTZ a n d SMALL, J.A.O.S., 1934, 56,
SMALL a n d COHEN, J.A.G.S., 1931, 1738.
5 3 , 2214. 11. SMALL and Y U E N , ibid., 1936, 5 8 , 192.
FKEUSTO, M E L B E E , and SCHLESINGEB, 12. andMoBKis, ibid., 1934,56, 2159.
J. pr. Chem., 1920, 101, 1. 13. and MALLONEE, J. Org. Chem.,
SMALL and TTJBNBTJLL, J.A.G.S., 1937, 1940, 5, 350.
59, 1541. 14. GOTO a n d A B A I , Bull. Chem. Soc.
6. a n d MOBBIS, ibid., 1933, 5 5 , Japan, 1942, 17, 113.
2874. 15. Arm., 1941,547, 194.
MAN Ni on and LOW^NIITOIM, Arch. 16. SMALL and RAPOPOBT, J. Org. Chem.,
rharm., 1020,258, 2015. 1947, 12, 284.
1
K NOLIi AND Ot)., JJ. Jt.-P. U4,IiOS 17. RAPOI'OUT and B O N N E B , J.A.O.S.,
(1022); /'W/. IB, IBlH. 1001,73,2872,
OH. i x T H E D E S O X Y C O D E I N B S A N D T H E I R D E R I V A T I V E S 165
18. K A B B E B a n d W I D M A E K , HeIv. Chim. 41. GOTO a n d SUDZUKI, Bull. Chem. Soc.
Acta, 1951, 34, 34. Japan, 1929, 4, 244.
19. W E I G H T , Proc. Roy. Soc, 1871, 19, 42. K O N D O and OOHIAI, Ann., 1929, 470,
371, 504. 224.
20. J.O.S., 1871,404. 43. OOHIAI a n d HAKOZAKI, J. Pharm. Soc.
2 1 . SMALL a n d COHEN, J.A.C.8., 1931, Japan, 1930, 50, 360.
53, 2227. 44. G B B W E , MONDON, a n d N O L T E , Ann.,
22. CAHN, J.G.S., 1926, 2652. ' 1949, 564, 161.
23. SMALL a n d COHEN, J.A.O.S., 1932,54, 45. GOTO a n d MITSUI, Bull. Chem. Soc.
802. Japan, 1931, 6, 197.
24. LTJTZ a n d SMALL, ibid., 1934, 56, 1741. 46. andSHiSHiDO.ibid., 1935,10,252.
25. ibid. 2466. 47. SMALL, Y U E N , a n d E I L E B S , J.A.C.S.,
26. S P E Y E B and KOULEN, Ann., 1924, 1933, 55, 3863.
438, 34. 48. H O F F M A N N - L A R O O H E AND C O . , Brit.
27. GATES a n d T S O H T O I , J.A.G.8., 1950, Pat. 451,203.
72, 4839. 49. Brit. Pat. 454,747.
28. BENTLBY, unpublished results. 50. D. R.-P. 630,680 (1936); Frdl. 2 3 ,
29. MOSETTIG, COHEN, and SMALL, 563.
J.A.C.S., 1932, 54, 793. 51. D. R.-P. 631,098 (1936); Frdl. 2 3 ,
30. H I L L , Dissertation, Erankfurt-am- 564.
Main, 1925. 52. WABNAT, U.S. Pat. 2,087,134 (13 J u l y
31. B U S C H a n d SCHMIDT, Ber., 1929, 6 2 , 1937).
2612. 53. SMALL, F A B I S , a n d MALLONEE, J. Org.
32. S P E Y E R a n d S A B B E , ibid., 1924, 57, Chem., 1940, 5, 334.
1404. 54. SOHBYVER and L E E S , J.O.S., 1900,
33. GOTLAND a n d ROBINSON, J.O.S., 1923, 1024.
980. 55. W B I G H T , Pharm. J. Trans., 1871, 1 ,
34. Mem. Proc. Manchester Lit. 867.
Phil. Soc., 1925, 69, 79. 56. ibid. 2, 84.
35. SPETEB. and KBATJSS, Ann., 1923, 57. ibid. 131.
432, 233. 58. Chem. News, 1871, 23, 302.
36. a n d R O S E N M J L D , Ber., 1925, 5 8 , 59. SMALL, U.S. Pat. 1,980,972 (13 N o v .
1113. 1934).
37. and SIEBEBT, ibid., 1921,54,1519. 60. and EABIS, J.A.O.S., 1934, 56,
38. OOHIAI a n d K O N D O , J. Pharm. Soc. 1930.
Japan, 1926, 538, 99. 61. ibid., 1935, 57, 364.
39. .ibid., 1929, 568, 91. 62. RAPOPOBT a n d B O N N E B , ibid., 1951,
40. K O N D O a n d OOHIAI, Ber., 1930, 63, 73, 5485.
646.
X
CODEINONE, 0-CODEINONE, AND T H E I R
DERIVATIVES
T H E secondary alcoholic group in codeine [i] can be oxidized by
potassium permanganate in acetone [1], and by chromic acid in sul-
phuric [1] or acetic [2-3] acid to carbonyl, giving the ketone codeinone
[n], also obtained by the oxidation of codeine methyl ether [4]. The
same ketone is produced by the oxidation of isocodeine [5], showing t h a t
the latter differs from codeine only in the spatial arrangement of the
alcoholic group. ^-Codeinone [in] results from the oxidation of ift-
codeine [5-7] and allo-i/r-codeine [5-6], which are thus also an epimeric
pair of alcohols [iv]. The yields of ketone are poor, due to side reactions,
the instability of the products in acid solution, and the difficulty of
separating them from other degradation products.
R E A R R A N G E M E N T IN ACID
Like thebaine [v], which is in the same state of oxidation, codeinone
[n] undergoes rearrangement in acid solution, though it is more stable
than the former, being recovered in 80 per cent, yield after standing for
fifteen minutes in concentrated hydrochloric acid at 15-20 C. [9]. I t
is converted to /3-methylaminoethanol and 3-methoxy-4:6-diacetoxy-
phenanthrene (identified by conversion to 3:4:6-trimethoxyphenan-
threne [14] identical with an authentic specimen [15]) on heating with
acetic anhydride [14]; to morphothebaine [ix] by concentrated hydro-
chloric acid at 100 C. [14]; to thebenine [x, R = H] by hot dilute aque-
ous hydrochloric acid or methebenine [x, R = Me], by hot dilute
methanolic hydrochloric acid [14]; and to metathebainone [xi] on
reduction with stannous chloride and hot concentrated hydrochloric
acid [16]. With the exception of the product of acetic anhydride
degradation these rearrangement products are the same as those ob-
tained from thebaine under the same conditions [17-20] and the reac-
tions are in both cases believed to involve the primary intermediate
[xn] which has not yet been isolated [21]. The mechanisms of the
transformations are discussed in Chapters X X I I I and XXV.
REDUCTION
(a) Catalytic hydrogenation of codeinone using palladium [13] or
Eaney nickel [3] as catalyst affords dihydrocodeinone [vm], identical
with the product prepared in other ways (see below).
(b) Electrolytic reduction in sulphuric acid with a lead cathode,
reduction with sodium hydrosulphite or hydrazine [28], and reduction
of the oxime [1], have all been reported to give codeine, but the sodium
hydrosulphite and hydrazine reductions have been reinvestigated by
Findlay and Small [3], who obtained only complex transformation
products and suggest that Hill's starting material [28J (much more
CH. X CODEINONE 169
0 O
/NMe -NMe ,NMe
Mev
N-NO y1
^S? O"
HO
OMe
[XX] [XXI] [XXII] [XXIII]
^-CODEINONE
f/t-codeinone [ i n ] r e s u l t s from t h e o x i d a t i o n of i/-codeine [ 5 - 7 ] a n d
allo-^-codeine [5-6]. I t is k e t o n i c , giving a n o x i m e [6] a n d s e m i c a r b a -
zone [ 6 - 7 ] , a n d t h e k e t o n e is a r ^ - u n s a t u r a t e d , as is s h o w n b y t h e f o r m a -
t i o n of a s e m i c a r b a z i n o - s e m i c a r b a z o n e [ x x i v ] b y t h e a d d i t i o n of semi-
c a r b a z i d e t o t h e 6 : 7 - d o u b l e b o n d o n s t a n d i n g for several h o u r s w i t h
excess of t h e r e a g e n t [7]. I t is s u b s t a n t i a l l y m o r e s t a b l e t h a n codeinone,
b u t is d e g r a d e d b y h e a t i n g w i t h acetic a n h y d r i d e t o 3 - m e t h o x y - 4 : 8 -
d i a c e t o x y p h e n a n t h r e n e (identified b y conversion t o 3 : 4 : 8 - t r i m e t h o x y -
p h e n a n t h r e n e [5], identical w i t h a n a u t h e n t i c specimen [39]) a n d /3-
m o t h y l a m i n o e t h a n o l , t h o u g h t h e m a i n p r o d u c t of t h i s r e a c t i o n is
t r i a c e t y l t h e b e n i n e [ x x v ] [6]. W i t h c o n c e n t r a t e d h y d r o c h l o r i c acid
i/r-codeinone is c o n v e r t e d t o phenolic s u b s t a n c e s , t h o u g h i t is s t a b l e i n
d i l u t e acid [6]. T h e m e t h i o d i d e t o o is m o r e s t a b l e t h a n t h a t of codei-
n o n e , a n d is c o n v e r t e d t o a phenolic b a s e C 1 9 H 2 1 O 3 N (decomp. 235 C.)
MeO MeO
/NMe /NMe
0Ac
NII1-OO-NII.Nif " ^ " " N . N H ' C O N H J NAcMe ^
IXXlVJ [XXVJ XXVI]
OH. x ^-CODEINONE 171
by alkalis, b u t on heating with alcohol a t 160 C. it is degraded to
3-methoxy-4:8-dihydroxyphenanthrene [6, 23].
STRUCTURE
i/i-Oodeine was originally thought to contain a reactive methylene
group as it condenses with benzaldehyde in the presence of sodium
ethoxide [7, 23], forms an isonitroso-derivative, and condenses with
diazonium salts [23]. Presumably these reactions arise from an isomeric
form [xxvi], production of which via the enol form would be favoured
in alkaline solution [25]. Lutz and Small have shown t h a t codeine will
condense with benzaldehyde under the same conditions, and doubt
whether any reliance can be placed on this reaction as indicating the
presence of a reactive methylene group in this series [7].
REDUCTION
As i/r-codeinone contains a 6:7-double bond and is in effect an allylic
ether it can, like i/r-codeine, give both phenolic and non-phenolic pro-
ducts on reduction.
(a) As with s/i-codeine reduction of the hydrochloride in glacial acetic
acid over platinum oxide favours mainly non-phenolic reduction, the
product being dihydro-</<-codeinone [xxvn], which is identified by its
reduction to dihydro-i/t-codeine-A [xxvni] by sodium and alcohol, no
dihydroallo-i/(-codeine being formed [7].
(6) Hydrogenation in neutral or weakly acid solution with a palladium
catalyst affords tetrahydro-i/<-codemone [xxix] [7, 28] which is further
reduced by sodium and alcohol to tetrahydro-i/t-codeine [xxx], the latter
being obtained directly from i/i-codeinone by sodium and alcohol re-
duction. I n no case do derivatives of allo-i/r-codeine result from these
reductions [7].
Speyer and Rosenfeld on reduction of 14-bromocodeinone [ x x n ] with
sodium hydrosulphite obtained an amorphous halogen-free base t h a t
was converted by hot alkali to a crystalline, ketonic, tertiary base
C 18 H 31 O 3 N t h a t they suggested was dihydro-i/f-codeinone [40], b u t its
properties do not agree with those of the latter [7] and its nature
remains obscure.
MeO MeO
/NMe NMe
[XXXIVJ
DIHYDROCODEINONE, DIHYDRO-^-CODEINONE,
AND T H E I R DERIVATIVES
PREPARATION
Dihydrocodeinone [vm], obtained by the catalytic reduction of
oodeinone [3, 13], is best prepared in other ways.
(a) Contrary to a statement by Merck and Co. [45] it cannot be p r e -
parod by the oxidation of dihydrocodeine [xxxv] with chromic acid or
potassium permanganate [13, 46]. I t can, however, be obtained from
dihydi'ocodeine in 83 per cent, yield by Oppenauer oxidation with
potassium tertiary butoxide and benzophenone in boiling benzene, and
tho morphine analogue results in the same way from dihydromorphine
OH. x DIHYDROCODEINONE, DIHYDRO-0-CODEINONE 173
in 71 per cent, yield. In contrast to this only 3 per cent, of [vni] can
be obtained by Oppenauer oxidation of dihydroisocodeine, and a similar
difference between the two epimers exists in the i/i-series, dihydroallo-i/<-
codeine-A [xxxvi] giving 40 per cent, dihydro-i/r-codeinone, whilst
dihydro-j/r-codeine-A is recovered unchanged. This susceptibility to the
Oppenauer oxidation is parallel to the physiological activity of the
alkaloids in which codeine can be paired with allo-i/r-codeine and >p-
codeine with isocodeine [47].
CHr0
[XLI]
BECKMAHN TEASSI1OEMATION
The Beckmann transformation of dihydrocodeinone oxime was in-
vostigatod by Schopf [68] in an attempt to determine the point of
attachment of the carbon end of the ethanamine side-chain. If the point
of attachment is C-13 [XLIV] tho product of transformation should be
an aldoliydo [XLV], whoroae if it is C-C [XLTX] the product Rliould bo a
CH. x DIHYDROCODEINONE, DIHYDR0-.//-C0DEIN0NE 175
ketone [L]. The requisite proof of the nature of the rearrangement
product was not directly forthcoming, so recourse was made to the
further Beckmann transformation of its methyl ether oxime. This,
assuming a C-13 attachment of the side-chain [XLVI], should yield a
PQCU -. HO MeO
orSOCI;
NMe OHC HO-N-C NMe
NHC
IIO-N
[XLIV] [XLV] [XLVI]
SOCI2
MeO MeO'
MeO MeO
HpFMANN
DEGRADATION
/NMe, -NMe
[XLVIII] [XLVII]
MeO
POC l 3>
OrSOCI2
NMe NMe
HO-N
[XLIX]
HOOC
NC
[LIII] [LII]
REDUCTION
(a) Dihydrocodeinone [63], its antipode [73-74], and the substituted
dihydrocodeinones and dihydromorphinones [38, 65] can be catalytically
roduced over platinum oxide in pyridine to the corresponding dihydro-
oodoinos and dihydromorphines, with no trace of the epimeric isocodeine
types.
OH. x DIHYDROCODEINONE, D I H Y D R O - ^ - C O D E I N O N E 177
(6) Sodium amalgam reduction proceeds with opening of the cyclic
ether and reduction of the carbonyl group, giving dihydrothebainol-A,
identical with that prepared in the same way from dihydrothebainone
[33] and epimeric with that obtained by the catalytic reduction of
codeinone [3].
(c) Clemmensen reduction converts dihydrocodeinone to tetrahydro-
desoxycodeine [LVI], which is almost certainly the product of Clem-
mensen reduction of dihydrothebainone [33, 75-76] (see Chap. XV).
(d) Reduction occurs when dihydrocodeinone and dihydromorphi-
none are heated with formaldehyde and calcium oxide in methanol,
aldol condensation also taking place, the products being 7:7-bis-
(hydroxymethyl)dihydrocodeine [LVII, R = Me] and 7:7-bis-(hydroxy-
methyl)dihydromorphine [LVII, R = H] respectively [77].
HOFMAHH DEGRADATION
Hofmann degradation of dihydrocodeinone methiodide affords dihy-
drocodeinone methine [LVIII] [55] which can also be prepared by the
hydrolysis of dihydrothebaine methine [LIX] [78], and by the catalytic
rearrangement of a-codeimethine [LX] by boiling with Raney nickel in
alcohol [79]. It can be reduced to the dihydromethine, available by
the hydrolysis of dihydrothebaine dihydromethine and by the chromic
acid oxidation of a-tetrahydrocodeimethine [LXI] [78]. The cyclic
ether link of the methine [LVIII] and dihydromethine can be opened
by aluminium amalgam reduction in wet ether, giving dihydrothebai-
none methine [LXII] and dihydromethine respectively [78].
MANNICH REACTION
As dihydrocodeinone contains the system COCH2 it was
expected to undergo the Mannich reaction, and indeed after heating
with dimethylamine hydrochloride and formaldehyde no dihydrocodei-
none could be recovered, and only 40 per cent, of the product was
crystalline. Under the same conditions 1-bromodihydrocodeinone (in
which the reactive position of the aromatic nucleus is blocked, thus
preventing any nuclear condensation) gave a 90 per cent, yield of
crystalline material, also obtained when diethylamine hydrochloride
was used in the reaction. The product cannot be sublimed, evidently
being dimolecular, and has been allotted the structure [LXVI, R = Br],
i.e. 7:7'-methylenebis-(l-bromodihydrocodeinone). I t is converted to
7:7'-methylenebis-(dihydrocodeinone) [LXVI, R = H] by catalytic
reduction, and this is identical with the crystalline material obtained
from dihydrocodeinone. A 5 : 5 ' or 5:7'-linkage is of course also possible,
but the 7:7' union was considered to be most likely as it is the least
hindered. No reaction occurs if triethylamine is substituted for the
socondary amine, so that formation of a complex between the latter and
- CIT1T
I IJXVTJ LLXVU] LLXVUT]
DIHYDROCODEINONE, DIHYDRO-0-CODEINONE 179
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Refs.
7:7-bis-hydroxymethyldihydro-
morphine . . . . . 282-283d. 77
Dihydrometacodeinone . 196-201 MeOH needles 63
oxime . . . . . 176-180 MeOH 63
1-bromodihydrometacodeinone 241-246 EtOH + 63
CHCl,
14-hydroxycodeinone \ see L
tlap
YVTTT
111
14-bromocodeinone / - ^* '
6-methyIdihydrocodeine, etc.: see Chap. IV.
6-methyldihydromorphine: see Chap. I.
AIkyldihydrocodeinonesandmorphinones: see Chap. XEX.
BIBLIOGRAPHY TO CHAPTER X
1. A O H a n d K N O B B , Ber., 1903, 36, 3067. 29. S P E Y E B , SELIG, a n d H E I L , Ann., 1923,
2. MBBOK AND C O . , D. R.-P. 408,870 430, 1.
(1923); FrAl. 14, 1303. 30. S K I T A , N O E D , R E I C H E B T , and STUKAET,
3. F I N D L A Y a n d SMALL, J.A.C.8., 1950, Ber., 1921, 54, 1560.
72, 3247. 3 1 . F I N D L A Y a n d SMALL, J.A.G.8., 1950,
4. M E R C K AND C O . , D. R.-P. 421,217 72, 3249.
(1923); Frdl. 15, 1515. 32. SCHNEIDER, Dissertation, Jena, 1906.
5. K N O B B and H O B L E I N , Ber., 1907, 4 0 , 33. OCHIAI, J. Pharm. Soo. Japan, 1929,
4889. 49, 91.
6. -ibid., 2032. 34. S P E Y E B a n d W A L T H E B , Ber., 1930, 6 3 ,
7. L U T Z a n d SMALL, J.A.O.8., 1935, 5 7 , 852.
2651. 35. F B B U N D , ibid., 1906, 39, 844.
8. K N O B U , Bur., 1906, 39, 1409. 36. GttncLAND and ROBINSON, Mem. Proa.
9. SCHOPF a n d H I B S C H , Ann., 1931, 4 8 9 , Manchester Lit.Phil.Soo., 1925,69,79.
224. 37. F B E U N D and S P E Y E B , J. pr. Chem.,
10. SCHMID and KABBEB, HeIv. Chim. 1916, 94, 135.
Acta, 1950, 33, 863. 38. L U T Z and SMALL, J. Org. Chem., 1939,
11. STOBK, J.A.O.S., 1951, 7 3 , 504. 4, 223.
12. SMALL and BROWNING, J. Org. OMm., 39. PSOHORB and BUSOH, Ber., 1907, 40,
1939, 3 , 618. 1995.
13. MANNIOH and L6WENHEIM, Arch. 40. S P E Y E B and R O S E N P E L D , ibid., 1925,
Pharm., 1920, 258, 295. 58, 1117.
14. K N O B B , Ber., 1903, 36, 3074. 4 1 . B E N T L E Y and ROBINSON, J.O.S., 1952,
15. PSCHOBB, S E Y D E L , and STOHBEB, 947.
ibid., 1902, 4 5 , 4400. 42. F I E S E B and F I E S E R , Natural Products
16. K N O B B , ibid., 1905, 3 8 , 3171. Related to Phenanthrene.
17. H O W A B D , ibid., 1884, 17, 527. 43. MOBRIS a n d SMALL, J.A.O.S., 1934,
18. H E S S E , Ann., 1870, 153, 47. 56, 2159.
19. F E E U N D a n d H O L T O F F , Ber., 1899,32, 44. PSCHOBK, Ann., 1910, 373, 15.
168. 45. MEBCK AND C O . , D. R.-P. 415,097
20. PSCHORR, ibid., 1905, 3 8 , 3160. (1923); Frdl. 15, 1518.
21. R O B I N S O N , Nature, 1947, 160, 815. 46. F R E U N D , M E L B E B , and SOHLESINGEB,
22. K N O B B , Ber., 1904, 37, 3499. J.pr.Chem., 1920,101, 1.
23. andHoBLEiN, ibid., 1907,40,3341. 47. RAPOPOBT, NAUMANN, BISSELL, and
24. GULLAND and BOBINSON, J.O.S., B O N N E B , J. Org. Chem., 1950, 15,
1923, 998. 1103.
25. CAHN a n d ROBINSON, ibid., 1926, 908. 48. K N O L L AND C O . , D. R.-P. 365,683
26. S O H 6 P P a n d BORKOWSKY, Ann., 1927, (1921); Frdl. 14, 1301.
458, 148. 49. D. R.-P. 380,919 (1922); Frdl. 14,
27. R O B I N S O N a n d SALTEB, unpublished 1302.
work. 50. Arch. Pharm., 1923,261, 140,
28. HtU-, DiBHortation, Frankfurt-am- 51. D. R.-P. 607,931 (1934); Frdl. 21,
Main, 1025. 652.
182 CODEINONE, ^-CODEINONE, AND DERIVATIVES OH. X
52. KNOLL AND CO., D. R.-P., 617,238 68. SOHOPF, Ann., 1927, 4 5 2 , 411.
(1934); Frdl. 22, 583. 69. U.S. Pat. 1,731,152 (8 Oct. 1929).
53. D. R.-P. 623,821 (1934); Frdl. 22, 70. Deut. Med. Wochschr., 1929, 5 5 ,
584. 302.
54. W E I S S and W E I N E B , J. Org. Chem., 7 1 . TIFPENEAU, Bull. Soc. Ohvm., 1915 (4),
1949, 14, 194. 17, 67.
55. FEETTND, SPBYEB, and GUTTMANN, 72. SABGENT and SMALL, J. Org. Chem.,
Ber., 1920, 5 3 , 2250. 1951, 16, 1032, footnote 2.
56. KNOLL AND CO., D. R.-P. 441,613 73. GOTO, Proa. Imp. Acad. (Tokyo), 1940,
(1923); Frdl. 15, 1517. 16, 403.
57. Brit. Pat. 225,824 (7 Dee. 1923). 74. and A B A I , Ann., 1941, 547, 194.
58. GOTO and SHISIIIDO, Bull. Chem. Soe. 75. K O N D O and OCHIAI, Ber., 1930,63,646.
Japan, 1935, 10, 597. 76. SMALL a n d COHEN, J.A.C.S., 1932,
59. S P E Y E K and S A B B E , Ber., 1924, 57, 54, 802.
1404. 77. MANNIOH and SCHULTE, Arch. Pharm.,
60. SOHOPF and P F E I I T E E , Ann., 1930, 1938, 276, 593.
483, 157. 78. W I E L A N D and K O T A K E , Ann., 1925,
61. BOBHBINGEK-SOIIN, D. R.-P. 533,692 444, 69.
(1929); .FnM. 18, 2870. 79. BENTLEY, unpublished results.
62. GOTO, Ann., 1931, 489, 86. 80. CAHN, J.C.S., 1930, 702.
63. SOHOPF and P E B B E Y , ibid., 1930, 483, 81. SMALL and RAPOPOBT, J. Org. Chem.,
169. 1947, 12, 284.
64. SMALL, F I T C H , a n d SMITH, J.A.O.S., 82. BOEHBINOMB-SOHN, D. R.-P, 479,104;
1936, 58, 1457. Frdl. 16, 2484.
65. TTTBNBULL, and F r r c n . J. Org. 83. R A P O P O B T and SMALL, J. Org. Chem.,
OAeTO., 1938, 3 , 204. 1947, 12, 834.
66. GOTLAND, J.C.S., 1928, 702. 84. S P E Y E B a n d R O E L L , Ber., 1930, 6 3 ,
67. K O N D O and IKAWA, Ber., 1932, 6 5 , 539.
1214. 85. K I N G , Analyst, 1931, 56, 498.
A D D E N D U M TO C H A P T E R X
Codeinone [A] has now been shown t o result in 30-40 per cent, yield
from t h e Oppenauer oxidation of codeine; i/f-codeinone cannot be pre-
pared in the same way from !/(-codeine.
The phenolic substance previously stated t o be formed when codei-
none is allowed to stand in hydrochloric acid, to have the composition
C18H2]O4ISr [3], and to be phenolic has now been identified as 8-hydroxy-
dihydrocodeinone [B], which is formed from codeinone by the addition
of a molecule of water to the double bond. Reduction of [B] catalytically
or with lithium aluminium hydride affords 8-hydroxydihydrocodeine
I C], which is not oxidized by periodates, thus eliminating formula [D]
for the parent ketone.
MeO. MeO-, MeO MeOx
_/NMe .NMe
OH HO'
LAJ LBJ
CH. X ADDENDUM 183
The erroneous statement that these two new bases were phenolic was
based upon a diazo-coupling reaction during which other changes must
occur (Findlay and Small, J.A.C.8., 1951, 73, 4001). Acetolysis of [B]
yields 3-methoxy-4:6-diacetoxyphenanthrene.
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Ref.
8-hydroxydihydrocodeinone 201 BtOAc sheaves -136 20 ? -| &2
hydrochloride . . . . 186-189 H2O prisms O
oxime . . . . . 274 BtOH prisms "*i
oxime hydrochloride . 261-5 BtOH prisms SS
2:4-dinitrophenylhydrazone hydro- aS
chloride . . . . . 220-230 EtOH prisms
8-hydroxydihydrocodeine 207 BtOAc -115 20 ? CO O
hydrochloride . . . . 238-5-240 EtOH
Findlay a
methiodide . . . . 250 MeOH needles
+ BtOAc
diacetyl ester . . . . 149-5- EtOAc tablets
150-5 J
XI
THEBAINE
THEBAiNE was discovered by Pelletier and Thiboumery during an
investigation of the alkaloids of opium, and, being thought to be an
isomer of morphine, was called paramorphine [1-3]; the name thebaine
was subsequently suggested by Couerbe [4].
0COUKKENCE
Thebaine appears in Papaver somniferum after narcotine, codeine,
morphine, papaverine, and narceine [5]; the amount in opium is always
small, varying between 0-2 and 0 8 per cent. [6-7], though a substan-
tially higher figure (up to 2-68 per cent.) has been recorded for Man-
churian opium [8]. Unlike morphine and codeine it is also found in
Papaver orientale, which contains thebaine as t h e only alkaloid during
periods of great vegetative activity, but only an isomer of totally
different constitution (isothebaine, Chap. XXIV) is found during
periods of withering and rest of the plant [9-11].
ISOLATION
(a) The aqueous extract of opium is treated with sodium acetate and
the precipitated narcotine and papaverine collected, the filtrate con-
centrated to small bulk with sodium acetate when narceine is precipi-
tated and removed, thebaine being finally isolated from the filtrate as
its sparingly soluble salicylate. I n this way 90 per cent, of the alkaloid
can be extracted [12-13].
(6) The concentrated aqueous extract of opium, diluted with an
equal volume of water, is treated with ammonia and left for twenty-four
hours, when all the narcotine and morphine are precipitated. The
remaining alkaloids are extracted by benzene, from which thebaine and
codeine are removed by dilute acetic acid and the former precipitated
by the addition of sodium carbonate to the acetate solution [14].
(c) The liquid remaining after the extraction of morphine by other
processes is treated with slaked lime a n d the calcium precipitates
leached with benzene, from which thebaine, narcotine, and papaverine
can be recovered [15].
Other methods of isolation and purification are given by Busse and
Busse [16] and by Willsteadt [17]. Barbier [18] has given a critical
and detailed aocount of the methods available for the extraction of
alkaloids from opium.
CH. X I THEBAINE 185
PHYSICAL PROPERTIES
Thebaine crystallizes from absolute or dilute alcohol in rectangular
plates associated in tufts, an illustration of which is given by Dean and
Brady [19]; on sublimation at 135 C. it is obtained as needles and at
160 C. also in cubes and prisms [20]. I t can be recrystallized from
alcohol, is readily soluble in benzene [21], chloroform [3], and pyridine
[22], but very sparingly soluble in petroleum [23]. The base can be
sublimed at atmospheric pressure [20] and in vacuo [24-27]. Vacuum-
sublimed thebaine has m.p. 192-5 C. The molten alkaloid forms a glass
on cooling [28]. Crystal density measurements have been made by
Schroder [29]. The specific rotation of the base has been recorded as
-218-64/15 D C , -216-36/22-5 C , -215-5/25 C , and of the hydro-
chloride as ~163-25/15 0. [30].
DETECTION
The following colour tests have been recorded for thebaine:
Reagent Colour References
cone. H 2 SO 4 red s- yellow- 31-32
cone. H2S04+conc. HNO3 red 33
cone. H2S04+H-CHO red 34
cone. H 2 SO 4 -)- sodium molybdate red 34
cone. H 2 SO 4 +ammonium vanadate red 34
cone. H 2 SO 4 -I-KIIeO 4 brown 35
cone. H 2 S0 4 +< 2 NH dark red-brown > green 32
cone. H N O 8 colourless '* yellow 32
60 min.
> dk. yellow
cone. HCl orange-red (characteristic)
cone. HCl. Reduce+excess zinc, 2-3 drops intense purple 36
of solution in 2-3 ml. cone. H 2 SO 4
H O A c + P b 0 2 , filter orange-red 37
H O A c + P b O 2 , filter, add cone. H 2 SO 4 golden yellow 37
Basic magnesium hypochlorite+HOAc red ring at interface 38
layered on to cone. H 2 SO 4
ZnCl 2 +dil. HCl. Evaporate with base on yellow 39-41
porcelain
,. , , evaporate , ,
HCI+a-nitroso -/J-naphthol light green > violet 32
C u S O 4 + 2 5 % HCl green 32
H g C l 2 + 2 5 % HCl yellow > grey 32
BiCl 3 +HCl yellow 32
E v a p . + SnCl 2 , then m o i s t e n + 4 0 % K O H black 32
E v a p . +SbCl 3 , then m o i s t e n + 4 0 % K O H yellow 32
Hg 2 (NO 3 ), black in 30 min. 32
2% aqueous furfurol red 34
Benzoquinone in hot benzene deep orange; fades with ap- 42-44
pearance of lemon-yellow
prisms
Methiodide+benzoquinono in hot CHCl 3 orange ppt. in 5 min. 36
SbCl0 weak blue -* colourloss 45-46
Iodine monouhlorido ppt. ovolves iodino on hoating 47
186 THEBAINE CH. X I
Colour tests are also given by Fulton [48]. Precipitation tests [49-53]
and microprecipitation tests [54] have also been devised.
ESTIMATION
The estimation of thebaine in the analysis of opium is described by
Klyachkina [55] and Anneler [56]. The alkaloid has been estimated in
opium residues by condensation with benzoquinone, isolation of the very
sparingly soluble adduct, and iodimetric titration of this in chloroform
solution. This method is reported to be accurate to 0-5 per cent., pro-
vided resins, dyeing substances, and phenolic alkaloids are first re-
moved [57]. Thebaine can also be estimated as its silicotungstate [53]
or salicylate [54].
COMPOSITION
The empirical formula of thebaine was variously given as C17H18O3N"
[3], C 15 H 27 O 4 N 2 [4], C 25 H 14 O 3 N [58] before the correct percentage com-
position, corresponding to C 19 H 21 O 3 N, was determined by Anderson
[59-61] and by Hesse [31]. Thebaine is a tertiary base, readily forming
quaternary salts [62-64], reacts alkaline to litmus, and gives stable salts
from solutions of which the base is not precipitated by neutral sodium
acetate [65].
DEGRADATION
Alkaline degradation of thebaine methiodide was stated by Howard
and Roser [66] to give trimethylamine and a substance of composition
C 14 H 12 O 3 , but Freund [63] showed that loss of the nitrogen-containing
side-chain occurs, the basic product being in fact tetramethylethylene-
diamine. Loss of the side-chain with production of phenanthrene
derivatives also takes place when the base or the methiodide is heated
with acetic anhydride [67-68] and benzoyl chloride [69], when the
products are acetylthebaol [i, R = Ac] and benzoylthebaol [i, R =
<j> CO] respectively. (Beckett and Wright [70] obtained only a resin on
heating thebaine with acetic anhydride.) Thebaol [i, R = H] results
from the hydrolysis of these compounds and also from thebaine and
ethanol or sodium ethoxide at 150-160 C. [71]; it is no doubt the pro-
duct of Hofmann degradation.
Acetylthebaol [i, R = Ac] can be oxidized to a quinone [n] without
loss of groups, showing t h a t the 9:10 positions are free from substituents
[67-68], and methylthebaol [i, R = Me] [72] was shown to be identical
with 3:4:6-trimethoxyphenanthrene by synthesis of the latter [73].
In this way the positions of the oxygen functions in thebaine were
established and the base identified as a derivative of a partially hydro-
gonated phenanthrene.
On the basis of the degradation of thebaine to derivatives of thebaol
and j8-(liitiotliylan)inoothanol (Chap. XXVII) tho oxazine formulae
OH. X I THEBAINE 187
[in] and [iv] were advanced for the alkaloid [63, 67-68], /3-dimethyl-
aminoethanol being assumed to arise by hydrolytic scission of the oxa-
zine ring; but this theory was abandoned when metathebainone (see
below), in which all three oxygen atoms were accounted for in methoxyl,
phenolic hydroxy], and carbonyl groups, was found to give /3-dimethyl-
aminoethanol on degradation to a phenanthrene derivative [74].
HYDROLYSIS
Thebaine [v] is an enol ether and though fairly stable in cold dilute
acid is hydrolysed to codeinone [vi] on standing with N. sulphuric acid
for several weeks in the cold or six to seven minutes at 100 C. [75], and
codeinone can also be isolated from the orange-red solution of thebaine
in concentrated hydrochloric acid [76]. I n this way the relationship of
t h e alkaloid to codeine and morphine was established. The yield of
codeinone is very poor ( < 7 per cent.), doubtless as a result of the ease
with which thebaine undergoes rearrangement in acid solution.
ACID TRANSFORMATIONS
(a) If the orange-red solution of thebaine in concentrated hydrochloric
acid, from which no thebaine can be recovered, is heated in sealed
vessels at 80-90 C. the colour slowly fades and morphothebaine [vil]
(Chap. X X I I I ) is formed [62, 66, 77].
(b) Thebaine is completely converted to thebenine [VIII] (Chap.
XXV) on boiling for l | - 2 minutes with dilute hydrochloric acid [31, 77].
(c) Reduction of thebaine with stannous chloride and hot concen-
trated hydroohloiio acid affords motathobainone [ix] (Chap. XVI)
188 THEBAINE OH. X I
R E A C T I O N W I T H H A L O G E N S AND H Y D B O G E N PEROXIDE
Bromination of thebaine in dilute hydrobromic acid affords bromo-
thebaine and bromothebaine tetrabromide [62]. Bromination in glacial
acetic acid, however, takes a different course resulting in production of
14-bromocodeinone [ x m , R = Br] [86]. 14-Chlorocodeinone [xin,
R = Cl] is obtained in 80 per cent, yield by the action of iodobenzene
dichloride ^ICl 2 on thebaine [87]. 14-Bromocodeinone is converted on
attempted preparation of its oxime to the oxime of 14-hydroxycodei-
none [ x m , R = OH] [86, 88], and the latter ketone is formed directly
from thebaine by the action of 30 per cent, hydrogen peroxide on the
base in boiling glacial acetic acid [88-92], or of potassium dichromate on
the base in dilute acetic or sulphuric acid [88-90, 93-94]. The fact t h a t
14-hydroxycodeinone does not contain the system COCH 2
whilst 14-hydroxydihydrocodeinone does, caused Gulland and Robinson
to modify the bridge-structure [xiv] earlier proposed for thebaine [95]
to the now-accepted [v] [96], from which 14-bromo- and 14-hydroxy-
codeinone are formed by the addition of bromine or hydrogen peroxide
to the ends of the conjugated diene, to give [xv, R = Br] or [xv,
R = OH], followed by loss of methyl bromide or methyl alcohol [96-97].
DIELS-ALDEB ADDITIONS
Thebaine behaves as an active conjugated diene in undergoing addi-
tion of maleic anhydride [42-43], benzoquinone [42-43], ! ^ - n a p h t h o -
quinone [42], and acrolein [102]. The adduct with benzoquinone
undergoes deep-seated rearrangement on heating for three hours with
concentrated hydrochloric acid to give flavothebaone [43-44] (see
Chap. X X I ) .
REDUCTION
The reduction of thebaine and the chemistry of its reduction products
are dealt with in Chapters X I I , X I I I , XIV, XV, and XVI.
OZONOLYSIS
When ozone is passed through an aqueous solution of thebaine
hydrochloride and the resulting base precipitated a 60 per cent, yield of
a-thebaizone [xix] is obtained [110-12]. This substance contains two
methoxyl groups and one carbonyl group, and is the methyl ester of an
aldehydo-acid, though Faltis [113] claimed t h a t it does not give the
Angeli-Rimini reaction. I t gives a somicarbazone [110] and jp-nitro-
phenylhydrazone [112] and roduoes cold ammoniaoal silver nitrate
190 THEBAINE CH. X I
HO-
HO
MISCELLANEOUS REACTIONS
(a) Thebaine undergoes a reaction with nitrosyl chloride, organic
nitrites, and nitrosyl sulphuric acid when its salts are treated with these
reagents in methyl or ethyl alcohol, the products being the same (if the
same alcohol is used) whatever the nitrosating agent. With thebaine and
nitrosyl chloride two isomoric substances are obtained, one alkali-
soluble and one alkali insoluble. Tho reaction in ethyl alcohol is
]02 THEBAINE OH. X I
ORIPAVINE
In 1935 an alkaloid named oripavine having the composition
C18H21O3N was isolated from Papaver orientale [124] and subsequently
from Papaver bracteatwm [125]. It was shown to contain one OMe,
one NMe, and one phenolic OH group [124], and was eventually
converted to thebaine [v] by methylation with diazomethane [126]
and is in fact 3-0-desmethylthebaine [xxxvn]; it bears the same
relationship to morphine as thebaine does to codeine. On boiling with
OH. X I ORIPAVINE 193
THEBAINE
CODEINE
4O
3-5
2
CJ
O
Q
3O
2-5;
20OO 25OO 3OpO 35OO
WAVELENGTH A
F I G . 4.
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Thebame . . . . . 193 BtOH plates -218 6 15 BtOH 30
f-574 HjO 127
hydrochloride H 1 O H2O plates 1-163 6 15 H0 30
sulphate . . . . . cryst. 60-61
chromate . . . . prisms Sl, 49
dichromate . . . . needles 49
fluorocolumhate. -132 128
oxalate 6H2O . . . . prisms 31
birioxalate-H a O prisms
diphenylviolurate 123 129
meconate 6H 2 O. EtOH prisms
salicylate . . . . . 65
picrato 217 /3-ethoxy needles 101,130
ethanol
plafcintchloride . . . . amorph. 60-61
moUiiodldo . . . . 224 cyclo- prisms 36
hoxanono
mothobromido . . . . ,, 64
mnMiamalliylHiilpliuto. 64
oMilodlda ui'oit noodles 2
(1147.1
194 THEBAINE OH. X I
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Refs.
Thebaine N-oxide . . . . c. 80 100
N-oxide hydrochloride. 238-239 EtOH or needles 100
H2O
Bromothebaine . . . . amorph. 62
Jiromothebaine tetrahromide . amorph. 62
a-thebaizone . . . . . 125-126 MeOH yellow 110-12
crystals
hydrochloride . . . . cryst. 112
hydriodide . . . . 185-187 acetone 112
methiodide . . . . D.250-251 H 2 O + 112
MeOH
semicarbazone . . . . 202 BtOAc 110
(3-thebaizone . . . . . 151 MeOH yellow 112
crystals
1-bromo-a-thebaizone 147 MeOH 112
Thebaizonic acid . . . . D. 235 BtOAc .," 112
Thebaizonic acid methine 112
hydrochloride . . . . 260-27Od. 112
hydriodide . . . . 250-255 112
Hydroxydihydrothebaizonic acid 230-240d. 112
hydrochloride . . . . D.205-210 MeOH 112
methiodide . . . . D. 163 112
Hydroxydihydro-P-thebaizonic acid . D. c. 200 H2O + 112
MeOH
hydrochloride . . . . D. 260 112
/3-thebaizone carboxylic acid . D. c. 220 MeOH cubes 112
f208-209 yellow 114
Thebaizone dicarboxylic acid . U89-190<i rods 112
H2O
Desoxythebaizone . . . . 147 MeOH yellow 112
prisms
Dihydrodesoxythebaizone oil 112
methiodide . . . . 175-177 MeOH 112
methiodide . . . . 148-152 H2O 112
Dihydrodesoxythebaizonic acid 163-1650! 112
hydrochloride . . . . 236 237 112
Dihydrodesoxythebaizonic acid
methine . . . . . D. 195 112
methiodide . . . . 156-158 112
Dibydrothebaizone. c. 140 112
methiodide . . . . D.239-240 112
Acetyldihydrothebaizone 112
methiodide . . . . D. 250 112
Isodihydrothebaizon e 103-105 112
methiodide . . . . 147-148 112
Isodihydrothebaizonic acid 248-249 MeOH 112
hydrochloride . . . . D. c. 130 112
methiodide . . . . D.179-180 112
Tctrahydrothebaizonic acid 230-235 112
230-233
Thebaine+ NOCl+ EtOH W$ 238-240 115
Thebaine + NOOl+MeOH 240-242 115
Oripavine . . . . . 200-201 -211'8 124
hydrochloride . . . . 244-245 124
methiodide . . . . 207-208 124
BIBLIOGRAPHY TO CHAPTER X I
1. P E L L E T I E B , J. Pharm., 1835 (2), 2 1 , 7. MAOHIGUOHI, J. Pharm. Soc. Japan,
555. 1926, 529, 185.
2. Compt. Rend., 1835, 1, 11. 8. ABIMA a n d I W A K I B I , Bept. Inst. Sd.
3. Ann., 1835, 16, 38. Res. Manchoukuo, 1938, 2 , 221.
4. CouBRBE, ibid., 1836, 17, 166. 9. GADAMBB, Z. angew. Ohern., 1913, 2 6 ,
5. Kirouosoii, Arch. Pharm., 1910, 248, 625.
1530. 10. Ber., 1914,24, 35.
0. DnAaioNDOtiir, JHe TfeAlpflanzm 11. K a n , Arch. Pharm., 1914,252, 211.
(UltwkH, HUiUgurt, IH08). 12. Vvvacm, ibid., 1897,225, 343.
CH. X I THEBAINE 195
13. PLUGGE, Bee. Trav. OHm., 1887,6,157. 52. GOTLAND a n d MACBAE, J.O.S., 1932,
14. KANBWSKAJA, J. pr. Ohem., 1924 (2), 2231.
108, 247. 53. STBUGATZKII and ZILBEEA, Byull.
15. ISHIKAWA a n d MABTTTA, Bull. Hyg. Nauch.-Issl. Khim.-Farm. Inst.,
Bes. Inst. Japan, 1929, 3 5 , 19. 1931, 203.
16. B U S S E and BTTSSE, Khim,. Farm. 54. WAGBNAAB, Pharm. Weekblad, 1927,
Prom., 1933, 127. 64, 472.
17. WlLMTnADT, Swed. Pat. 98,873 (14 55. KLYACHKINA, Khim. Farm. Prom.,
May 1940). 1933, 203.
18. BABBIEB, Ann. pharm. Franc., 1947, 56. ANNELEB, Festschrift Emil O. Barell,
5, 121; Ohem. Aba., 1948, 4 2 , 1023. 1936, 344.
19. D E A N a n d B B A D Y , J.G.8., 1865, 34. 57. K A N E W S K Y A , YASKINA, and M I T E Y A -
20. B L Y T H , ibid., 1878, 313. GiNA, J. Applied Ohem. U.S.S.R.,
21. KtrBLY, Jahresber. Fortschr. Ohem., 1945, 18, 374.
1866, 823. 58. K A N E , Ann., 1836, 19, 7.
22. D E H N , J.A.O.S., 1917, 39, 1399. 59. ANDEESON, J. pr. Ohem., 1852, 5 7 ,
23. TAYLOB, Allen's Oomml. Org. Anal., 358.
1912, vi. 363. 60. Trans. Roy. Soc. Edinburgh, 1853,
24. K E M P F , J. pr. Ohem., 1908, 78, 201. 20, 335.
25. HBIDUSCHKA and MEISNEB, Arch. 61. Ann., 1853,86, 179.
Pharm., 1923, 2 6 1 , 102. 62. H O W A R D , Ber., 1884, 17, 527.
26. BOTOLFSEN a n d PATJLSSEN, B M B . SOC. 63. FBETTND, ibid., 1894, 2 7 , 2961.
GHm., 1946, 390. 64. GBEBBB,Z).iJ.-P. 228,246 (1910); JFVcM.
27. JANOT and CHAiGENEAtr, Oompt. Rend. 10, 1211.
1947, 225, 1371. 65. PLUGGE, Arch. Pharm., 1886, 224, 993.
28. GATTBEET, ibid., 1913, 156, 1161. 66. H O W A B D and R O S E B , Ber., 1886, 19,
29. SCHEODEB, Ber., 1880, 13, 1070. 1604.
30. H E S S E , Ann., 1875, 176, 189. 67. F B E U N D and GOBBL, ibid., 1895, 2 8 ,
31. ibid., 1870, 153, 47. 941.
32. REICHABD, Pharm. Zentralhalle, 1906, 68. M I C H A E L S , and GOBBL, ibid.,
47, 623. 1897, 30, 1357.
33. COTJEBBE, Ann. GHm. Phys., 1835 (2), 69. PSCHOBB and H A A S , ibid., 1906,39,16.
59, 136. 70. B E C K E T T a n d W E I G H T , J.G.S., 1876,
34. P F I S T E B , Ohem. Ztg., 1908, 32, 1494. 652.
35. MOKBANTZA, Bull. /S1OCv Ohim. Boy. 71. K N O B B , Ber., 1904, 3 7 , 3499.
Tougoslav., 1932, 3 , No. 3., 171. 72. VONGBBIOHTBN, ibid., 1902, 35, 4410.
36. B E N T L E Y , ROBINSON, and WAIN, 73. PSCHOBB, SEYDEL, and STOHEEB,
J.O.S., 1952, 958. ibid., 4400.
37. D E E B , Pharm. Monatsh., 1925, 6, 117. 74. K N O B B and PSCHOBB, ibid., 1905, 3 8 ,
38. D A V I D , Pharm. Ztg., 1925, 70, 969. 3172.
39. JOBISSBN, Z. anal. Ohem., 1880, 19, 75. a n d HOBLEIN, ibid., 1906, 3 9 ,
357. 1409.
40. CZTJMPELITZ, Arch. Pharm., 1881, 219, 76. SOHOPF a n d H I B S O H , Ann., 1931, 489,
63. 224.
41. Pharm. Post, 1881, 14, 47. 77. FBETTND a n d H O L T O F F , Ber., 1899,
42. SANDEBMANN, Ber., 1938, 7 1 , 648. 32, 168.
43. SCHOPF, VON GOTTBEEG, and P B T B I , 78. PSCHOBB, PFAOT, and HEBSCHMANN,
Ann., 1938, 536, 216. ibid., 1905, 38, 3160.
44. B E N T L E Y and DOMINGUEZ, Un- 79. SOHOPF and BOBKOWSKY, Ann., 1927,
published work. 458, 148.
45. SMITH, Ber., 1879, 12, 1420. 80. K N O B E , Ber., 1903, 36, 3074.
46. Ohem. News, 1879, 4 0 , 26. 81. ibid., 1905,38, 3171.
47. DITTMAB, Ber., 1885, 18, 1612. 82. ROBINSON, Proc. Boy. Soc, 1947,
48. FULTON, J. Assoc. Official Agr. Ohem., 135 B, v-xix.
1920, 12, 434. 83. Nature, 1947, 160, 815.
49. PLCTGOJJ, Arch. Pharm., 1887,225,793. 84. VON B B A U N , Ber., 1914, 47, 2312.
50. Bee. Trav. Ohim., 1887, 6, 210. 85. S P B Y B E and ROSBNJTBLD, ibid., 1925,
81. CuriN/tTiiisatj and Pour, Ann. Sci. 58, 1125.
Univ. JUM}/, 1040, i, 26, B03. 80. Frauwj), ibid., 1000,39, 844.
196 THEBAINE OH. X I
ether under the influence of hot sodium ethoxide [3]) as it yields /3-
thebainone [VII], having the 'abnormal' configuration at C-14, on
hydrolysis [7]. However, the conditions required for the production of
[VII] from /J-dihydrothebaine are precisely those required for the pro-
duction of the same ketone from dihydrothebaine-</> [3] and the reaction
is of no structural significance. Moreover, yS-dihydrothebaine readily
absorbs two moles of hydrogen on reduction giving dihydrothebainol-
6-methyl ether [vin] [7], whereas thebainone-A enol methyl ether [vi]
absorbs only one mole of hydrogen and gives an enol ether [3].
[vin] (18 per cent.). The first of these was found to be identical with the
product of reduction of thebainone-A enol methyl ether [vi], and
dihydrothebainone obtained by Speyer and Freunds [15] by the reduc-
tion of thebaine in neutral solution doubtless arose from hydrolysis of
this enol ether during isolation of the product. The dihydrothebainol-6-
methyl ether from this reduction appears to be identical with that
derived from /J-dihydrothebaine. It can be methylated at the phenolic
group (by Rodionov's method [23]), but none of the dihydrothebainols
[11, 24-28] have yet been converted to a dimethyl ether for purposes of
comparison [3].
Hydrogenation in neutral solution at 50-60 C. proceeds much more
rapidly than at the room temperature. The activity of the various
catalysts, which may vary greatly in different specimens prepared in
apparently the same way, may markedly affect the course of reduction
of thebaine [18].
T H E M E C H A N I S M OF R E D U C T I O N
The catalytic hydrogenation of thebaine evidently proceeds by four
competing mechanisms that can be explained as follows. The conjugated
6 5 4 3 2 1
system OCC=CC=C can undergo initially 1:2, 1:4, 1:6, or
5:6 addition of hydrogen, giving as final products dihydrothebaine,
tetrahydrothebaine, dihydrothebainone A6-enol methyl ether (dihydro-
thebainone in acid solution), and dihydrothebainol-6-methyl ether
respectively. 3:6-addition of hydrogen occurs in the sodium and liquid
ammonia reduction, giving dihydrothebaine-^.
Dihydrothebaine [xi] results from 1:2-addition of hydrogen and is
not further reduced under mild conditions, as hydrogenation ceases
when a considerable amount of this still remains in the mixture.
Tetrahydrothebaine [xiv] arises as a result of l:4-addition of
hydrogen giving the intermediate [xvn], the isolated double bond of
which is immediately further reduced.
As in the iff- and allo-i/<-codeine series (Chap. IV), reduction of the
double bonds of thebaine [i] without opening of the cyclic ether, giving
[xi] and [xiv], is favoured by hydrogenation of the hydrochloride rather
than of the base [10-14, 16-17].
Dihydrothebainone [xn] or its A6-enol methyl ether [x] is produced
in considerable quantity in all reductions of thebaine even under mild
conditions, and cannot arise from further reduction of dihydrothebaine.
It undoubtedly arises from 1:6-reduction of the conjugated system to
give thebainone-A enol methyl ether [vi], which then suffers further
1:4-reduction to dihydrothebainone A6-enol methyl ether [x], the latter
boing hydrolysed in acid solution to dihydrothebainone [xn]. This
meohanism was suggostod by Schopf and Winterhalder [14], but Small
OH. XII T H E R E D U C T I O N OF T H E B A I N E 201
5
and Browning wished to modify it so as to make the A -enol ether [ix]
the second intermediate on the basis of an erroneous concept of the
nature of the reduction of thebainone-A enol methyl ether [3].
MeO. MeO MeO.
(XIV)
TETRAHYDROTHEBAINE
MeO'
,NMe
Il l__l I I Ij" I Ij'
1
MeO^-f^ MeO' ^
(Vl) (X) (XII)
THEBAINENg3 THEBAINONE-A DIHYDROTHEBAINONE DIHYDRO-
V^ENOLMETHYLETHER A6-ENOLMETHYL ETHER THEBAINONE
MeO
HO'
114-ADDITION
Me /NMe
MeO MeO'
B I B L I O G R A P H Y TO C H A P T E R X I I
1. F R E U N D a n d H O L T O F F , Ber., 1899,32, 20. KNOLL AND C O . , D. R.-P., 441,613
168. (1923); J?V(. 15, 1517.
2. and SPEYER, ibid., 1916,49,1287. 21. Brit. Pat. 225,824 (7 Dec. 1923).
3. SMALL a n d BROWNING, J. Org. Chem., 22. W I E L A N D a n d K O T A K E , Ber., 1925,
1939,3, 618. 58, 2009.
4. B E N T L E Y a n d R O B I N S O N , Experientia, 23. RODIONOV, Bull. Soc. Chim., 1926 (4),
1950, 6, 653. 39, 305.
5. and W A I N , J - C S . , 1952,958. 24. S P E Y E R a n d S I E B E R T , Ber., 1921, 5 4 ,
6. STORK, J.A.G.S., 1951, 73, 504. 1519.
7. SCHMID and K A R R E R , HeIv. Chim. 26. OOHIAI and K O N D O , J. Pharm. Soc.
Acta, 1950, 3 3 , 863. Japan, 1926, 538, 99.
8. OLDENBERG, Ber., 1911,44, 1829. 26. K O N D O and OOHIAI, Ann., 1929, 470,
9. D. R.-P. 260,233 (1911); Frdl. 11, 224.
996; Houben, 4, 58. 27. OOHIAI, J. Pharm. Soc. Japan, 1929,
10. F R E U N D , SPEYER, and GUTTMANN, 568, 91.
Ber., 1920, 5 3 , 2250. 28. GATES a n d TSOHUDI, J.A.C.S., 1950,
11. SKITA, NORD, REICHEBT, and STU- 72, 4839.
KART, ibid., 1921, 54, 1560. 29. SOHOEF a n d BORKOWSKY, Ann., 1927,
12. W I E L A N D a n d K O T A K E , Ann., 1925, 452, 248.
444, 69. 30. ibid., 458, 173.
13. ScHdPF and WINTERHALDER, ibid., 31. ROBINSON, Proc. Roy. Soc, 1947,
1927,452, 232. 1 3 5 B , v-xix.
14. SMALL, F I T O H , and SMITH, J.A.O.8., 32. Nature, 1947, 160, 815.
1936, 58, 1457. 33. PSOHORR, PFAmr, a n d HERRSOHMANN,
15. S P E Y E R , F R E U N D , F R E U N D , F R E U N D , Ber., 1905, 38, 3160.
and FREUND, D. R.-P. 338,147 34. SOHOPF a n d H I R S O H , Ann., 1931, 4 8 9 ,
(1915); Frdl. 13, 881. 224.
16. BOEHRINGER, Brit. Pat. 285,404 (28 35. B E N T L E Y and ROBINSON, J.O.S., 1952,
May 1929). 947.
17. BOEHRINGER-SOHN, D. R.-P. 503,924 36. and W A I N , ibid., 1952, 972.
(1927); Frdl. 17, 2350. 37. GOTO and SHISHIDO, Bull. Chem. Soc.
18. BBNTLEY, Unpublished results. Japan, 1935, 10, 507.
19. CAHN, J.C.S., 1933, 1038.
XIII
D I H Y D R O T H E B A I N E AND
TETRAHYDROTHEBAINE
DIHYDROTHEBAINE
M I L D catalytic reduction of thebaine hydrochloride in aqueous or
dilute acetic acid solution using a platinum [1] or colloidal palladium
catalyst [2-6] results in saturation of the 8:14-double bond and pro-
duction of dihydrothebaine [i]. The yield is never high, as considerable
amounts of dihydrothebainone [n] and tetrahydrothebaine [in] are
produced simultaneously, not by further reduction of dihydrothebaine,
which is stable under these conditions.
CHO
[XXXIII] [XXXIV] [XXXV] [XXXVI]
TETRAHYDROTHEBAINE
Tetrahydrothebaine [in] was first prepared by Schopf and Winter-
halder [5] and shown to be identical with dihydromorphine dimethyl
ether. It is best prepared from thebaine by hydrogenation of the
hydrochloride in glacial acetic acid over platinum oxide [22-23], or of
the base in ethanol over W. 6 Raney nickel [24]. It can be demethylated
to dihydromorphine by hydriodie acid or aluminium chloride [22-23].
The Hofmann degradation has not been studied, but hydrogenation of
a-oodeimothine methyl ether [xxxix] affords a-tetrahydrocodeimethine
mothyl other [XL], which is tetrahydrothebaine dihydromethino [25].
CH. XIII TETKAHYDROTHEBAINE 209
Oldenberg [26] prepared a substance that he believed was tetra-
hydrothebaine, but it was a mixture of substances. The action of
cyanogen bromide on this mixture gave an ill defined substance, m.p.
approximately 200 C. [27].
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
Dihydrothebaine . . . . 162-163 BtOAc (plates) -266-9 20 benzene 1-3, 5-6
prisms
hydrochloride . . . . cryst. 1
picrate . . . . . 235 BtOH rods 1
acid citrate . . . . D. 88-90 EtOH + 2
benzene
methiodide-2H 2 O 231 HaO prisms 2
methiodide (anhyd). . 257 EtOH prisms 2
N-oxide . . . . . oil 1
N-oxide picrate . . . . 209-210 needles 1
Cyanonordihydrothebaine 258-259 HOAc 1
Dihydrothebaine methine 134-135 BtOH 1, 16
methiodide . . . . 243 1
Dihydrothebaine dihydromethine oil 17
hydrochloride . . . . cryst. 17
methiodide . . . . 217-222 17
6-mothoxy-13-vinyltetrahydro- / 123-124-5 16
morphenol methyl ether \ 120-121 BtOH plates 15
6-keto-13-vinylhexahydromorphenol
methyl ether . . . . 149 BtOH prisms 15
6-keto-13-ethyloctahydromorphenol
methyl ether . . . . 113 EtOH rods 15
semicarbazono . . . . 191 EtOH 15
6-methoxy-13-vinylhexahydro-
morphenol methyl ether 119 prisms 3
6-methoxy-13-ethylhexahydro-
morphenol methyl ether 65-66-5 petrol prisms -134-0 20 EtOH 16
methyl ether . . . . 16
6-keto-13-ethyloctahydromorphol /154-155 -48-0 20 EtOH 16
methyl ether (.148-150 EtOH prisms 3, 15
isomer . . . . . oil 3, 17
methyl ether . . . . 114-116 subl. -54-2 20 BtOH 16
3-methoxy-4-hydroxy-13-ethyl-octa-
hydrophenanthrene-A 6: '-methyl
enolate . . . . . 171-173 MeOAc prisms + 23-8 20 EtOH 16
3:4-dimethoxy-6-amino-13-ethyl-
octahydrophenanthrene
a-baae . . . . . oil 16
^ - h y d r o c h l o r i d e . . . . 138-144 PrOH prisms + 12-4 20 EtOH 16
and
211-213
<*-perchlorate 197-199 Bt.O + plates + 8-4 20 EtOH 16
MeOAc
/3-base . . . . . oil 16
^-hydrochloride . . . . 253-255 PrOH needles -58-9 20 BtOH 16
(3-perchlorate . . . . Bt 2 O + prisms -63-8 20 BtOH 16
Et s CO
3:4-dimethoxy-6-dimethyIamino-13-
ethyloctahydrophenanthrene
-base . . . . . 76-5-78 subl. 16
a-perchlorate . . . . 224-225-5 Et 2 O + needles + 18-8 20 EtOH 16
acetone
a-methiodide . . . . 242-244 16
/3-baso oil 16
/3-perchlorate . . . . 230-231-5 Et,6 + prisms -64-3 20 EtOH 16
acetone
/3-mothiodido . . . . 263-264 16
8:4-dlmothoxy-18-ethyl-
0:10:5:18:8:14-octahydro-
phonftnthrnno, or Isomer . . 110-5-112 potrol prisms + 6-8 20 EtOH 16
8:4-rtlmoUiQxy-J 8-oUiyl-
6:0:7:8:0:10:111: U-ooUliydro-
lihuimiiilii'omi . . . . 78-15-80 llbl. -32-3 20 16
0447.1 1J
210 DIHYDROTHEBAINEANDTETRAHYDROTHEBAINE OH. xm
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Mefs.
3:4-dimethoxy-5:6 (or 6:7)-di-
hydroxy-13-eUiyloctahydro-
phenanthrene
(
150-5-152 dry Et11O
137-142 petrol } " -47-6 20 EtOH 16
P- 119-121 dry Et 2 O
oil -11-7 20 EtOH 16
rxXXIV] or [XXXV] ? -53-0 20 16
Totrahydrothebaine: see dihydro codeine methyl ether, Chap. IY.
Dihydro codeinone derivatives: see Chap. X .
Dihydrothebainone derivatives: see Chap. XV.
B I B L I O G R A P H Y TO CHAPTER X I I I
1. FBETJND, SPEYEB, and GUTTMANN, 14. BENTLBY, ROBINSON, and WAIN,
Ber., 1920, 5 3 , 2250. J.O.8., 1952, 958.
2. SKITA, NOBD, REICHEBT, and STTJ- 15. C A H N , i b i d . , 1930, 702.
K A B T , i b i d . , 1 9 2 1 , 5 4 , 1560. 16. S A B G E N T a n d S M A L L , J . Org. Chem.,
3. WIELAND and KOTAKE, Ann., 1925, 1951, 16, 1 0 3 1 .
444, 69. 17. W I E L A N D a n d K O T A K E , Ber., 1 9 2 5 , 5 8 ,
4. GOTLAND and ROBINSON, J.O.S., 2009.
1923, 1007. 18. B E N T L E Y a n d W A I N , J.O.S., 1 9 5 2 , 9 7 2 .
5. SCHOM? and WINTEBHALDEB, Ann., 19. S A B G E N T a n d S M A L L , Science, 1950,
1927, 4 5 2 , 2 3 2 . 112, 4 7 3 .
6. SMALL, FITCH, and SMITH, J.A.G.S., 20. G H O S H a n d R O B I N S O N , J.O.S., 1944,
1936, 5 8 , 1457. 506.
7. K N O L L A N D C O . , D. R.-P. 441,613 2 1 . W I E L A N D a n d S M A L L , Ann., 1928,
( 1 9 2 3 ) ; Frdl. 1 5 , 1517. 4 6 7 , 17.
8. Brit. Pat. 225,824 (8 D e o . 22. B O E H R I N G B - S 6 H N , D. R.-P. 503,924
1923). ( 1 9 2 7 ) ; .FnM. 1 7 , 2 3 5 0 .
9. G O T O a n d S H I S H I D O , Bull. Chem. Soc. 23. B O E H B I N G E B , Brit. Pat. 285,404 ( 2 8
Japan, 1935, 1 0 , 5 9 7 . M a y 1929).
10. S A B G E N T a n d S M A L L , J . Org. Chem., 24. B E N T L B Y , U n p u b l i s h e d w o r k .
1951, 16, 1032, f o o t n o t e 2 . 25. F A L T I S a n d S T J P P A N , Pharm. Monatsh.,
1 1 . S C H O M - , Deut. Med. Wochschr., 1929, 1923, 4 , 189.
5 5 , 302. 26. O I D E N B E B G , D. R.-P. 260,233 ( 1 9 1 1 ) ;
12. U.S. Pat. 1,731,152 (8 O c t . Frdl. 1 1 , 9 9 6 ; Houben, 4 , 5 8 .
1929). 27. H O M - M A N N - L A R O C H E A N D C O . , D.
13. S M A L L , T T T B N B U L L , a n d F I T C H , J . Org. R.-P. 2 8 6 , 7 4 3 ( 1 9 1 4 ) ; Frdl. 1 2 , 7 4 1 ;
Chem., 1938, 3 , 204. Houben, 4 , 5 8 8 .
XIV
D I H Y D R O T H E B A I N E - ^ AND
P- D I H YD R O T H E B A I N E
WHEN thebaine [i] is reduced by sodium and boiling alcohol [1-3], or
best by sodium in liquid ammonia [4-5], scission of the 4:5-oxygen
bridge occurs with the addition of two atoms of hydrogen and pro-
duction of a phenolic dihydrothebaine, for which the name dihydrothe-
baine-</> has now been adopted [5]. The sodium-ammonia reduction is
rapid, simple, and results in excellent yields of product. !Reduction
of thebaine with lithium aluminium hydride also yields a phenolic
base, ^-dihydrothebaine, which is isomeric with dihydrothebaine-^ [6].
Dihydrothebaine-^ was first allotted the structure [n] on the basis of
its reactions [3], and /3-dihydrothebaine the structure [in] with the
'abnormal' configuration at C-14 on the basis of its hydrolysis to j3-
thebainone-A [iv] [6]; thebainone-A enol methyl ether [in] with the
'normal' configuration at C-14, which results from the isomerization of
codeine methyl ether [v] under the influence of hot sodium ethoxide,
is known to give thebainone-A [iv, C-14 epimer] on hydrolysis [3].
REDUCTION
Dihydrothebaine-< absorbs only one mole of hydrogen on catalytic
reduction, yielding dihydrothebainone AB-enol methyl ether [ix], which
is identical with the product of sodium and liquid ammonia reduction
of the non-phenolic dihydrothebaine [x] [5]. (A compound of different
melting-point and specific rotation was prepared by Small and Brown-
ing [3] by the catalytic reduction of dihydrothebaine-<j> and allotted the
structure [xi] owing to a misconception of the structure of the latter.
I t is probably a mixture [5].) Dihydrothebainone [xn] is produced by
the hydrolysis of [ix] showing that no rearrangement of the thebaine
skeleton occurs during sodium and alcohol reduction [5].
r _ | __T| t /NHMe
MeO-' ' ~~~"
[XIII] [XIV] [XV]
(a) Mineral acid hydrolysis, first stated to give an ill defined sub-
stance called 'isocodeine' [1] (a bad name) and later 'a, coloured,
varnish-like substance' [3], has been shown to give thebainone-B [xrv]
[8]. This compound is only stable as a dry salt; the free base and the
damp salts readily degenerate to tars. I t is a /J: y-unsaturated ketone
and gives dihydrothebainone [xn] on reduction [8] (see Chap. XV).
(b) Hydrolysis with aqueous potassium bisulphate gives mainly
/3-thebainone-A [iv] with the 'abnormal' configuration at C-14, to-
gether with a small amount of thebainone-A [iv, C-14 epimer] and a
small amount of thebainone-C [xv] [3]. Thebainone-/? is doubtless an
intermediate in this hydrolysis, as it is converted to /J-thebainone-A on
standing in aqueous potassium bisulphate [8].
(c) Hydrolysis with sulphurous acid affords a poor and erratic yield
of thebainone-C, first tentatively allotted the formula [xiv] [3], but now
known to have suffered fission of the nitrogen-containing ring and to be
a secondary amine [xv] [8].
The hydrolysis of,fi-dihydrothebaine has not been extensively studied;
with aqueous potassium bisulphate it is converted to /3-thebainone-A
[iv] [6], but as dihydrothebaine-^ also gives /3-thebainone-A under the
same conditions the reaction cannot be regarded as having any structural
significance.
Thebainone-A enol methyl ether gives thebainone-A on hydrolysis
so readily t h a t no salts of the enol ether can be prepared even in an-
hydrous media [3].
Dihydrothebaine-^p methiodide undergoes hydrolysis with fission of
the nitrogen-ring on boiling with sulphurous acid [ 1,5] or mineral acid [5]
giving thebainone-B methine [xvi] (the melting points of the hydrolysis
product and its derivatives as recorded by Freund and Holtoff [1]
differ widely from those observed by the author [5]). This has been given
tho structure [xvi] on aooounb of tho similarity of its ultra-violet
214 D I H Y D R O T H E B A I N E - ^ AND /3-DIHYDROTHEBAINE OH. XIV
4.5. . .
THEBAINE (I)
DIHYDROTHEBAINE-(t) (VIlO
4O
*
W
O
O 3-5
3-0
25
2000 25OO 3500
WAVELENGTH
Fio. 5.
absorption spectrum to t h a t of /J-codeimethine [xvn] [5] (Fig. 6).
I t is also obtained by the hydrolysis of jS-dihydrothebaine methine
(see below), thebainone-B methiodide, and possibly /3-dihydrothebaine
methiodide [5]. The intermediate in all these reactions is doubtless
thebainone-B methiodide which, in its enolic form [xvin], allows \the
formation of a conjugated system by fission of the nitrogen ring with
the introduction of a 9:10-double bond. Neopine methiodide [xix],
which cannot develop a similar conjugated system, is unaffected by hot
acids [5].
McO'
HO
/NMeJ
4-5i
(J-CODEIMETHINE (XVII)
^-CODEIMETHINE (XXI)
THEBAINONE-B METHINE (XVI)
4O
S
g3-5
3O-
2-5
25OO 3000 3500
WAVELENGTH
FIG. 6.
The methyl ether of [xvi] arises from acid hydrolysis of dihydrothe-
baine-< methyl ether methiodide and /3-dihydrothebaine methyl ether
methine [5].
HOMANN DEGRADATION
Contrary to the statement of Freund and Holtoff [1], dihydrothe-
baine-<^> methiodide readily undergoes alkaline degradation with pro-
duction of a methine base [4-5], which is allotted the structure [xx]
and the name /3-dihydrothebaine methine, as its ultra-violet absorption
spectrum clearly indicates the conjugation of more than two double
bonds with the aromatic nucleus [5, 8] (Fig. 7). Migration of the 5:6-
double bond into conjugation with those at 8:14 and 9:10 doubtless
occurs under the influence of the hot alkali (compare the conversion of
a-codeimethine [xxi] to jS-codeimethine [xvn], Chap. VI). Mineral acid
hydrolysis of [xx] yields [xvi], and catalytic hydrogenation affords a
tetrahydrodorivativo [4-5], Hofmann degradation of dihydrothebaine-
(f> methyl other mothiodido gives tho methyl othor of [xx] [5, 9], whioh is
216 D I H Y D R O T H E B A I N E - ^ AND ,S-DIHYDROTHEBAINE OH. xiv
very unstable and spontaneously loses amine on standing [5]; it can
be hydrolysed to thebainone-B methyl ether methine [5].
MeO
[XXII]
4-5
p)-DIHYDROTHEBAINE METHINE(XXJ)
p>-CODEIMETHINE (XVIIl)
40
2
W
O
QJ
35
6 -METHQXYTHEBENTRIENE (XXIl)
3O
25OO 3000 35OO 40OO
WAVELENGTH A
FIG. 7.
MeO
-' yMcO
[XXIV] [XXV] [XXVI]
Migration of H -
Me Me
H^-OH "
[XXVII] [XXVIII] [XXIX]
Migration of M e -
-NMe8, /NMe 2
MeO Qrt^S MeO MeO--
[XXX] [XXXI] [XXXII] [XXXIII]
Solvent
for Crystal Specific
Compound m.p. C. reerystn. form rotation Temp. Solvent Refs.
Dihydrothebaine-c. 154 EtOAc+ prisms r+25-5 27 EtOH 3
petrol 1+81-4 18 EtOH 5
picrate 176d. EtOH + needles 5
benzene
methiodide-EtOH 155-160 EtOH prisms 1
methiodide 3H2O 75-80 H1O needles 1
methyl ether methiodide 192 EtOH 9
O-nootyldihydrothebaine-0 189 petrol prisms 5
- picrate . . . . . 18Od. (3-ethoxy- prisms 5
ethanol
/J-dihydrothebaine . . . . 171-172 Et 2 O + + 307-0 18 6
EtOH
picrate 6
methiodide . . . . Et 1 O + 6
pyridine
'J'hebainone-A enol methyl ether 154-156 EtOH granules + 9-6 22 EtOH 3
/S-dlhydrothebaine methine 99 MeOAc cubes 5
or petrol
picrate . . . . . 159 (decomp.) scarlet 5
prisms
methiodide . . . . oil 5
methoperchlorate 134 H1O + apple- 5
EtOH green
needles
/3-dihydrothebaine methyl ether
methine oil 5, 9
Totrahydro-(,8-dihydrothebaine
methine) . . . . . oil 00 20 EtOH 5
6-mothoxythebentrlene . 88 petrol yellow 5
prisms
Dihydrothebaine-< dihydromethine . 88-89 Et 2 O leaflets + 94-5 17 EtOH 11
methiodide . . . . oil H
methoperchlorate JH 1 O 253 H1O needles 11
Dihydrothebaine-0 methyl ether di-
hydromethine . . . . oil 11
4-hydroxy-S: 6-dimethoxy-13-ethyl-
7:13:9:10-tetrahydrophenanthrene oil 11
A'^-o-methoxythebendiene oil 11
The thebainones and their derivatives.
Dihydrothebainone and its deriva- see Cha p. XV.
tives. Tetradehydrothebenone
B I B L I O G R A P H Y TO C H A P T E R X I V
1. FKETJITO a n d H O L T O J T , Ber., 1899, 3 2 , 6. SCHMID and K A B B E B , HeIv. Chim.
168. Acta, 1950, 3 3 , 863.
2. a n d S P E Y E B , ibid., 1916,49,1287. 7. STOBK, J.A.G.8., 1951, 7 3 , 504.
3. SMALL and BBOWNING, J. Org. Chem., 8. BESTTLBY and W A I N , J.G.S., 1952, 967.
1939, 3, 618. 9. E B B U N D , Ber., 1905, 38, 3234.
4. B E N T L E Y a n d ROBINSON, Mxperientia, 10. ROBINSON, Unpublished work.
1950, 6, 353. 11. B E N T L E Y and W A I N , J.G.S., 1952, 972.
5. _ _ . an d WAIN, J.O.S., 1952, 12. SCHMID a n d K A B B E B , HeIv. GMm.
958. Acta, 1951, 3 4 , 19.
XV
THE THEBAINONES AND THEIR
DERIVATIVES
T H E term 'thebainone' is applied to ketones of the morphine group
having a phenolic hydroxy! at position 4 and a carbonyl group and one
double bond in ring C. Strictly they are not ketones related to thebaine
[i], which is an enol ether of codeinone [n], but to /3-dihydrothebaine
[ni] and dihydrothebaine-^ [iv]. Four thebainones are known, not
including metathebainone which is the product of a rearrangement of
the thebaine skeleton and has the basic side-chain attached to C-14;
it is discussed separately in Chapter XVI. References to 'thebainone'
in the literature prior to 1927 refer to metathebainone.
THEBAINONE-A
Thebainone-A [v] results from thebaine or codeinone when these
bases are reduced with stannous chloride and concentrated hydrochloric
acid under conditions different from those required for the preparation
of metathebainone, which nevertheless is formed at the same time in
small amount [I]. (A small amount of a by-product m.p. 156-158 C.
was also obtained during one reduction of thebaine [I].) Thebaine
hydrochloride and stannous chloride in acetic acid at 160 C. yield
methebenine [1] (see Chap. XXV).
Thebainone-A can also be prepared by the catalytic rearrangement
of codeine [vi] under the influence of palladized charcoal at 80 C. [2];
by the hydrolysis of thebainone-A enol methyl ether [vn] (prepared by
the rearrangement of codeine methyl ether on heating with sodium
ethoxide) [3]; by the hydrolysis of /?-ethylthiocodide [vin] (obtained by
the action of sodium ethoxide on bromo- or /3-chlorocodide) [4-8] (see
Chap. XVII) and, in small amount, by the hydrolysis of dihydrothe-
baine-^ [iv] [3].
Catalytic rodnotion of thobainono-A proceeds readily with formation
of dihydrothobainono [ix'j, wliioh is formed in considerable quantity in
220 T H E T H E B A I N O N E S AND T H E I R DERIVATIVES OH. x v
O-DESMETHYLTHEBAINONE-A
O-desmethylthebainone-A [xi], the morphine analogue of thebainone-
A, results from the catalytic rearrangement of morphine in the presence
of palladized charcoal at 80 C. [2]; it is doubtless identical with the
ketone obtained by the hydrolysis of /?-ethylthiomorphide [14-15].
Although it cannot be methylated to thebainone-A, on reduction it
yields O-desmethyldihydrothebainone [xn], which gives dihydrothe-
bajnone on treatment with diazomethane [2].
/J-THEB AINONE-A
This substance is tho main product of hydrolysis of dihydrothebaine-<
[ivj [3] and /3-dihydrothobbino [in] [10] with potassium bisulphate
OH. xv THETHEBAINONESANDTHEIRDERIVATIVES 221
solution. The isomerism of thebainone-A and /3-thebainone-A is not due
to the difference in position of the double bond, as the infra-red absorp-
tion spectra show t h a t both are a ^ - u n s a t u r a t e d ketones [13], and
moreover the isomerism persists after hydrogenation and when /?-
dihydrothebainone, the product of hydrogenation of /3-thebainone-A, is
degraded to a nitrogen-free product, at each stage of which compounds
are obtained t h a t are isomeric with those derived from dihydrothe-
bainone [3].
The cause of the isomerism is the asymmetric carbon atom C-14,
which in thebainone-A and its derivatives is configured as in codeine
but has the opposite configuration in /3-thebainone-A. Although the
latter could arise from /J-dihydrothebaine [in] by a 1:4-hydrolysis of
the system MeO C = C C = C , such a mechanism seems unlikely as it
cannot be operative in the hydrolysis of dihydrothebaine-</> [iv] during
which /3-thebainone-A must be formed by the isomerization of thebain-
one-B, a reaction t h a t has been independently realized [13] (see below).
No enol ether of /3-thebainone-A epimeric with thebainone-A enol
methyl ether [vn] has been prepared; /3-dihydrothebaine was first
thought to be such a compound [16] but subsequently was shown to
have the structure [in] [17].
THEBAINONE-B
Thebainone-B [xm] is best prepared as its hydrobromide by the
hydrolysis of dihydrothebaine-^ [iv] with alcoholic hydrobromic acid
[13], b u t it is also formed by the hydrolysis of the same base with
mineral acid in aqueous solution [13], a reaction first reported to give
an ill-defined substance, 'isocodeine' [18], and later said to give a
'coloured, varnish-like substance' [3]. Thebainone-B appears to be
stable only as its salts in the dry state, the damp salts and free base
readily degenerating to brown tars [13]. The ultra-violet spectra of
thebainone-A, /3-thebainone-A, and thebainone-B closely resemble
those of dihydrothebaine-< and codeine, whilst t h a t of thebainone-C is
widely different (Fig. 8) and the frequencies of the carbonyl-absorption
in the infra-red indicate that whereas thebainone-A and /3-thebainone-A
are a !^-unsaturated ketones, the unsaturation is /8:y- in thebainone-B
and thebainone-C [13]. On this evidence thebainone-B is allotted the
structure [xin]. I t can be catalytically reduced to dihydrothebainone
[ix], in which the configuration at C-14 is the same as in codeine [13]
(cf. the production of dihydrocodeine on reduction of neopine [xiv] [19]).
Thebainone-B is doubtless an intermediate in the hydrolysis of dihy-
drothebaine-^ to /3-thebainone-A, to which it is converted on standing in
aqueous potassium bisulphate for twenty hours,[13].
Hofmann degradation of thebainone-B has not beon attempted, but
thobainono-B mothino [xv] is formod when dihydrothobaine-^ meth-
222 T H E T H E B A I N O N E S AND T H E I R D E R I V A T I V E S OH. xv
4-5
4-O
Q
3-5
3-O
25
2000 25OO 3000 35OO
WAVELENGTH A
Eio. 8.
\ ^*
\ / \ B-CODEIMETHINE(XX)
4O
2
LO
O
Q
3-5
THEBAINONE-B METHINE(XV)
oc-CODEIMETHINE UXI)
3-O
THBBAINONE-C
This isomer is obtained in erratic yield by the hydrolysis of dihydro-
thebaine-< by sulphurous acid. Tt was initially allotted the structure
[xiit] [3], but has since been shown to have the structure [xxv], which is
allotted to the base on account of the ultra-violet absorption spectrum,
which indicates a highly conjugated system (Mgs. 8 and 9), and the
infra-red absorption, which indicates that the compound is a /J:y-
unsaturated ketone [13]. I t is apparently formed during the hydrolysis
/NMe
OMo
LXXVj LXXVi] Lxxviij [XXVIII]
OH. xv T H E T H B B A I N O N E S AND T H E I R D E R I V A T I V E S 225
of dihydrothebaine-0 independently of thebamone-B, which cannot be
isomerized to thebainone-C by sulphurous acid [13].
SlNOMENINE
This alkaloid, which can be obtained from the plant Sinomenium
acutum, is now recognized as the optical antipode of 7-methoxythe-
bainone [xxvi]. I t can be converted to the antipode of dihydrothebain-
one. Sinomenine and its derivatives are fully discussed in Chapter
XXVI.
14-Hydroxythebainone [xxvn], which results from the stannous
chloride reduction of 14-hydroxycodeinone [xxvin] [24], is discussed in
Chapter X V I I I .
DlHYBEOTHBBAINONE
Dihydrothebainone [ix], obtained by the catalytic reduction of
thebainone-A [v] [1] and thebainone-B [xm] [13], can be most con-
veniently prepared by the catalytic reduction of thebaine in acid solu-
tion [9-12, 25], and it can also be obtained by the hydrolysis of its two
enol ethers (see below). I t is a phenolic, ketonic, base, t h a t shows the
diazo-reaction in dilutions up to 1 in 2,000,000 [26-27], gives a methyl
ether [28], oxime [9], semicarbazone [29], and a benzylidene [30] and
piperonylidene [25] derivative. The optical antipode is produced by
the sodium amalgam reduction of sinomenine [xxvi] and is known as
desmethoxydihydrosinomenine [31].
and amyl alcohol [9], being hydrolysed during the isolation of the
product.
DIHYDROTHEBAINONE A6-ENOL METHYL ETHER
This enol ether [xxxi] is the product of catalytic or sodium amalgam
reduction of thebainone-A enol methyl ether [vil] [3], from which it
arises by 1:4-addition of hydrogen to the conjugated system, and it can
also be prepared by the hydrogenation of thebaine in neutral solution
[3]. I t is very readily hydrolysed to dihydrothebainone, which doubt-
less arises from this during the reduction of thebaine in acid solution.
(Dihydrothebainone was prepared by Speyer and Freunds [10] by the
reduction of thebaine in neutral solution and no doubt arose from the
enol ether by hydrolysis during the isolation of the product.)
R E D U C T I O N OF THE DIHYDROTHEBAINONES
(a) Catalytic hydrogenation of dihydrothebainone affords the alcohol
dihydrothebainol-B [xxxn] [11], which also results from the catalytic
reduction of codeinone [n] [33] (see Chap. X). The optical antipode of
this compound has been prepared in the sinomenine series [34-35], and
the C-14 epimer by the catalytic reduction of /3-dihydrothebainone [36].
(b) The C-6 epimer of dihydrothebainol-B results from the sodium
amalgam [35, 37] and sodium and liquid ammonia [38] reduction of
dihydrothebainone [ix], and the sodium amalgam reduction of dihydro-
codeinone [xxxni] [34]; it is also obtained as a by-product during the
electrolytic reduction of dihydrothebainone [39]. Its optical antipode,
desmethoxydesoxydmydrosinomeninol, has been prepared from sino-
menine [34-35, 40-42].
(c) The electrolytic reduction of dihydrothebainone was reported
by Speyer and Siebert [39] to give 'dihydrothebacodine', which was
alkali-insoluble, reacted with phosphorus pentachloride to give chloro-
dihydrothebacodide, reduction of which afforded desoxydihydrothe-
bacodine. On this evidence dihydrothebacodine was allotted the
structure [xxxiv] and the chloro- and desoxy-compounds structures
[xxxv] and [xxxvi] respectively.
(d) Clemmensen reduction of dihydrothebainone and of dihydroco-
doinone [xxxin] yields a compound of the same composition as, and
having tho same physioal properties as, dihydrothebacodine [34, 42-43].
OH. xv T H E T H E B A I N O N E S AND T H E I E D E R I V A T I V E S 227
Br
[XXXVII] [XXXVIII] [XXXIX] [XL]
B B O M I N A T I O N OP D I H Y D B O T H B B A I N O N E
Bromination of dihydrothebainone proceeds with the formation of
1-bromodihydrothebainone with one mole of bromine, 1:5-dibromodi-
hydrothebainone [xxxix] with two moles of bromine [45], and 1:5:7-
tribromodihydrothebainone [XL] with three moles of bromine [46].
Treatment of the 1:5-dibromo-compound [xxxix] with alkali results in
loss of hydrogen bromide and closure of the 4:5 ether bridge, the product
being l-bromodihydrooodoinone, reduotive denomination of which
affords dihydrooodoinorio [xxxm] [45, 47]; the Iattor oan bo converted
228 . THE THEBAINONES AND T H E I R DERIVATIVES CH. XV
NMe
NMe PB
CH
MeNH H
OH
[XLVI] [XLVII]
N-OH NH2 OH
[XLIX] [L] [LI]
H O F M A S N DEGRADATION OF DIHYDBOTHEBAINONE
The alkaline degradation of dihydrothebainone methiodide affords
dihydrothebainone methine [LII] [9], also accessible by the aluminium
amalgam reduction of dihydrocodeinone methine [LIII] [25]. I t can be
reduced catalytically to dihydrothebainone dihydromethine [LIV] [9],
which is best prepared by the catalytic reduction of dihydrothebaine
methine [LV] in dilute acetic acid [25]. ^-Dihydrothebainone can in the
same way be converted to /3-dihydrothebainone methine and ^-dihy-
drothebainone dihydromethine [3], the latter being most conveniently
prepared by the hydrogenation of thebainone-B methine [xv] [20-21].
0 N
OH 3 0- OsX
HO
LLXlVJ LLXVJ LLXVlJ LLXVIIJ
T H E T H E B A I N O N E S AND T H E I B D E R I V A T I V E S 231
DIMOLECULAR DERIVATIVES
The thebainones and their derivatives are phenols and can be oxi-
dized to dimolecular substances by gold or silver salts or potassium
ferricyanide (compare the oxidation of morphine to pseudomorphine,
Chap. I I I ) .
Thebainone-A may be oxidized to bis-l:l'-thebainone-A by 10 per
cent, gold chloride in 10 per cent, hydrochloric acid. This may be
hydrogenated to bis-1: l'-dihydrothebainone, which is also obtained by
the oxidation of dihydrothebainone with silver nitrate [52]. Bis-1: l'-
dihydrothebainone yields bis-1: l'-dihydrothebainone methine and
dihydromethine, (-f) bis-1: l'-(9:10-dehydrothebenone) and ( + ) bis-
1:1'-thebenone, the antipodes of which may all be prepared from
bis-1: l'-desmethoxydihydrosinomenine [62], on degradation.
Oxidation of sinomonine by potassium ferricyanide affords a mixture
of two bason, disinomonino and t/v-disinomenino, the first of which also
oooura with mnotmmiuo in nature [03-05J (see Chap. XXVI).
232 THETHEBAINONESANDTHEIRDERIVATIVES OH. XV
0
[LXXI] [LXXII] [LXXIII] [LXXIV]
ALKYLDIHYDROTHBBAINONES
When dihydrothebaine [LXXV, R = Me] and dihydrocodeinone enol
acetate [LXXV, R = Ac] are treated with Grignard reagents alkyldi-
hydrothebainones and isoalkyldihydrothebainones are obtained [66-
67]. The location of the new alkyl group in these is uncertain, but may
be either C-5 [LXXVI] or C-7 [LXXVH]. The products can be converted to
alkyl and isoalkyldihydrocodeinones, the enol acetates of which react
again with Grignard reagents to give, if the two alkyl groups introduced
are identical, the same dialkyldihydrothebainone [67]. These com-
pounds are discussed in detail in Chapter X I X , but it may here be
stated that methyldihydrothebainone and isomethyldihydrothebainone
have been degraded to the corresponding methine bases and to methyl-
9:10-dehydrothebenone [LXXVIII?] and isomethyl-9:10-dehydrothe-
benone [68].
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Sefs.
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
Dihydrothebainone methine hydrio-
dide . . . . . . 170-180 9
("240-243* OHCl8+
Bis-1: l'-dihydrothebainone methine. (. 252 prisms -45-1 19 MeOH 62
methiodide . . . . amorph. 19 62
Dihydrothebainone methyl ether
methine . . . . . 89-5 petrol 28
hydriodide . . . . 211-212 H8O columns 28
methiodide . . . . c. 189 MeOH 28
semicarbazone 184 EtOH needles 28
piperonylidene derivative . oil 28
("189-192*
1-bromodihydrothebainone methine . 1200-201 MeOH prisms + 8-0 17 46
methiodide . . . . 243 H8O 56
j9-dihydrothebainone methine . 183-184 H8O + needles -257-9 28 EtOH 3
EtOH
perchlorate . . . . 225-5-226 EtOH 3
picrate . . . . . 164-165 66% -181-1 27 acetone 3
EtOH
oxime . . . . . 160-162 50% 3
EtOH
Et 8 Of prismst + 67-8f 18 MeOH 55
Dihydrothebainone dihydromethine . ( 154-156
156-5f
H8O + needles 9,25
EtOH
perchlorate . . . . 233 28
picrate . . . . . 185-188 25
methiodide . . . . 226-229 MeOH prisms 9, 55
piperonylidene derivative . 179-181 25
Acetyldihydrothebainone dihydro-
methine picrate . . . . 188-192 25
Bis-1: l'-dihydrothebainone dihydro- /245-248* prisms - 32-5 20 CHCI8+ 62
methine \249-250 MeOH
Dihydrothebainone methyl ether
dihydromethine 70-5-72 petrol 28
hydriodide . . . . 224-225 H3O needles 28
perchlorate . . . . 216 28
methiodide . . . . oil 28
methoperchlorate 185-186 H1O needles 28
semicarbazone . . . . 176-178 Eton 28
1-bromodihydrothebainone dihydro- /175-177* 56
methine I 192 MeOH prisms -62-7 17 56
hydrobromide . . . . 257 56
methiodide . . . . 273f 56
Dihydrothebainone dihydromethine
A5-enol methyl ether . oil 23
^-dihydrothebainone dihydromethine 177-178 EtOH needles + 63-7 27 CHCl, 3
hydrobromide . . . . 260-260-5 EtOH needles + 24-0 28 H8O 3
perchlorate . . . . 232-5- H8O rods + 23-8 28 MeOH 3
233-5
picrate . . . . . 203-207 EtOH needles + 18-2 27 acetone 3
oxime and salts notcryst. 3
8:14:9:10-tetradehydrothebcnone .
248 dioxane prisms 21
/ 158* 62
() 9:10-dehydrothebenone I 113 prisms -206-9 18 55
(202-205" 62
( + ) Bis-1: l'-(9:10-dehydrothebenonc) 205-212 + 201-5 20 CHCl8+ 62
MeOH
/159-160 MeOH*
( + ) l-bromo-9:10-dehydrothebenone 1148-150 OHCl1 prisms + 187-3 17 acetone 56
/156-158"
( + ) 9 ?-bromo-9:10-dehydrothebenone 1127-130 + 112-7 17 acetone 56
(-)9:10-dehydrothebenone ketone furazanandderivs.: see Chap. X X VI.
, f 120* -78-6t 18 MeOH 55, 62
Thebenone . . . . . 1134-136 EtOH prisms + 64-6 22 EtOH 25, 69
oxime . . . . . 201-204 25
2:4-dinitrophonylhydrazone 228 dioxane prisms 21
JsonltrosoUiobonono 105 25
"Boniiylklonntliolionono . 162 25
l'lpnrnnylldonolliulMiiiuno 185-180 25
/250-25(1 i< CIIC1.-I
ISIs-I il'-tliolxmono. . . . \ 2!IiI ',', ,, -I ioa-j 20 MoOIl 02
* Jt uuumtilo. t Anllpot Id.
236 T H E THEBAINONES AND THEIR DERIVATIVES OH. XV
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
/191-193* plates*
1-bromothebenone MeOH needles + 23-3 56
X 70 17
Thebenone ketone . . . . 185-187 25
dioxime . . . . . 155-160 25
and 260
p-thebenone . . . . . 189-190 BtOH rods + 113-6 28 EtOH 3
oxime . . . . . 176-177 H1O + cubes + 30-6 28 EtOH 3
BtOH
L'iperonyIidene-/3-thebenone 189 0-ethoxy- plates 21
ethanol
Morphirane . . . . . 103 50% plates 21
EtOH
fl-morphirane . . . . 148 50% prisms 21
EtOH
Thobenane-JHjO . . . . 86 50% prisms 0-0 20 MeOH 21
EtOH
TIiebenane . . . . . 48-54 + 3-2 22 EtOH 61
5:6(or 6:7)-dehydrothebenane . 78 BtOH 70
O: I O-dehydrothebenane . 107-112 prisms + 175-5 22 EtOH 61
Derivatives of thebenone ketone furaz.ML : see Chap. XXVI.
Dihydrothebainol-A JH 2 O D.138-142 -46-2 28 EtOH 35, 39
hydrochloride . . . . D. 268 39
hydriodide . . . . cryst. 39
methiodide . . . . 280 H2OH- -24-3 29 MeOH 37
BtOH
Dihydrothebainol-A methyl ether . 181-182 39
methiodide . . . . 284-285 39
Dihydrothebainol-A methine oil 39
hydriodide . . . . 179-180 39
methiodide . . . . 281-282 39
Nitrogen free product from degrada-
tion of dihydrothebainol-A mothine oil 39
Dihydrothebainol-B 165 needles -36-5 20 EtOH 11
methiodide . . . . 273 EtOH 11
bhphenyhirethane 175 11
l)ihydrothebainol-B methyl ether oil -28-0 27 EtOH 36
hydrobromide . . . . 254'5-255 + 34-0 28 EtOH 36
methiodide . . . . 279-281 36
(1-dlhydrothebainol-B 165-5-168 -23-0 30 EtOH 36
/3-dihydrothebainol-B methyl ether . 152-5- -9-0 30 EtOH 36
153-5
- plcrate . . . . . 190-191 36
methiodide . . . . 243-245 36
7-hydroxydihydrothebainol 51
'rriacotyl-7-hydroxydihydrothebainoI 51
Dlliydrothebainol-6-methyl ether 140-5-142 subl. needles -23-4 27 EtOH 3, 18
methyl ether . . . . 3
Allcyldihydrothebainones and their dee radation products: see Chap. X CX.
Racemate.
B I B L I O G R A P H Y TO C H A P T E R XV
1. SOIIOPF and H I B S C H , Ann., 1931, 489, 10. S P E Y E B , EBETJND, FBETJND, FBETTND,
224. and FKKtTND, D. B.-P. 338,147
2. W B I S S a n d W E I N E B , J. Org. Chem., (1915); Frdl. 13, 881.
1949, 14, 194. 11. SKITA, N O B D , R E I C H E B T , a n d STTT-
3. SMALL a n d BBOWNING, ibid., 1939, 3 , KABT, Ber. 1921, 54, 1560.
618. 12. SCHOPP a n d W I N T E E H A L D B B , Ann.,
4. P S O H O B B , Ber., 1906, 39, 3130. 1927, 452, 232.
5. and R O L L E T T , Arm., 1910,373,1. 13. B E N T L E Y a n d W A I N , J.O.S., 1952,967.
6. ibid., 15. 14.PSOHOBB a n d H O P P E , Ann., 1910,373,
7. SMALL a n d MOBRIS, J.A.O.S., 1932, 45.
54, 2122. 15. W E I S S a n d W E I N E B , J. Org. Chem.,
H, . ibid., 1034, 56, 2159. 1949, 14, 194.
0. 'FiniiUNi), SL'WVIOII, and QUTTMANN, 16. SOIIMID and KABBEB, HeIv. Chim.
Bw,, 1020, 53, 2200. Acta, 1900, 33, 803.
OH. x v THE THEBAINONES AND THEIR DERIVATIVES 237
17. STOBK, J.A.G.S., 1951, 7 3 , 504. 45. SCHOPF and PFEIFFEB, Ann., 1930,
18. F E B O T D and HOI/TOFF, Ber., 1899, 3 2 , 483, 157.
168. 46. a n d HIBSOH, ibid., 1932,
19. VAN D U I N , ROBINSON, and SMITH, 492, 213.
J.G.S., 1926, 903. 47. BOEHBINGEB-SOHN, D. P.-P. 533,692
20. B E N T L E Y and R O B I N S O N , Experientia, (1929); Prdl. 18, 2870.
1950, 6, 353. 48. W A L L A C E , Ann., 1918, 414, 296.
21. a n d W A I N , J.G.S., 1952, 49. GOTO and NAMBO, Bull. Ghem. Soc.
958. Japan, 1930, 5, 73.
22. SCHOPF a n d BOBKOWSKY, Ann., 1927, 50. a n d SHIBASAKI, Ann., 1933, 5 0 3 ,
452, 248. 277.
23. B E N T L E Y and W A I N , J.C.S., 1952,972. 51. and ABAI, JSMH. Chem. Soc.
24. F B E U N D a n d S P E Y E B , J. pr. Ghem., Japan, 1942, 17, 113.
1916, 94, 135. 52. andOGAWA1J-TCTC., 1934,511, 502.
25. WiBBAND a n d K O T A K E , Ann., 1925, 53. K O N D O and IKAWA, Ber., 1932, 6 5 ,
444, 69. 1214.
26. GOTO, Bull. Ghem. Soc. Japan, 1929, 54. J. Pharm. Soc. Japan, 1932,
4, 103. 52, 777.
27. ibid., 1 9 3 0 , 5 , 3 1 1 . 55. GOTO, INABA, a n d SHISHIDO, Ann.,
28. CAHN, J.C.S., 1926, 2562. 1931, 485, 247.
29. GOTLAND a n d ROBINSON, ibid., 1923, 56. OGAWA, a n d SAITO, JBMW. Ghem.
998. Soc. Japan, 1935, 10, 481.
30. ibid., 1928, 702. 57. and MITSUI, ibid., 1931, 6, 197.
31. GOTO a n d SUDZUKI, JBMK. Ghem. Soc. 58. J. Chem. Soc. Japan, 1932,
Japan, 1929, 4, 244. 53, No. 7, 737.
32. SCHOPF a n d BOBKOWSKY, Ann., 1927, 59. Bull. Ghem. Soc. Japan,
458, 173. 1932, 7, 223.
33. FiNDiAY and SMALL, J.A.C.8., 1950, 60. HUANG-MINLON, J.A.C.S., 1946, 6 8 ,
72, 3247. 2487.
34. OOHIAI, J. Pharm. Soc. Japan, 1929, 61. GOTO and SHISHIDO, Bull. Ghem. Soc.
568, 91. Japan, 1935, 10, 252.
35. K O N D O a n d OCHIAI, Ann., 1929, 470, 62. MIOHINAKA, and SHISHIDO, Ann.,
224. 1935, 515, 297.
36. GATES a n d T S C H U D I , J.A.G.S., 1950, 63. J. Ghem. Soc. Japan, 1923, 4 4 ,
72, 4839. 795.
37. OOHIAI a n d K O N D O , J. Pharm. Soc. 64. Proc. Imp. Acad. {Tokyo), 1926,
Japan, 1926, 538, 99. 2,7.
38. B E N T L E Y and WAIN, Unpublished 65. and SUDZUKI, JSMH. Ghem. Soc.
results. Japan, 1929, 4 , 107.
39. S P E Y E B and S I E B E B T , Ber., 1921, 54, 66. SMALL, F I T C H , and SMITH, J.A.G.S.,
1519. 1936, 58, 1457.
40. GOTO a n d M I T S U I , JSMH. Ghem. Soc. 67. TUBNBULL, a n d F I T C H , J. Org.
Japan, 1930, 5, 282. Chem., 1938, 3 , 204.
41. ibid., 1931, 6, 33. 68. SABGENT, a n d BBALLEY, ibid.,
42. OOHIAI a n d HAKOZAKI, J. Pharm. Soc. 1947, 12, 847.
Japan, 1930, 50, 360. 69. MUNSTEB, HeIv. CMm. Acta, 1930,13,
43. K O N D O a n d OOHIAI, Ber., 1930,63, 646. 1046, footnote 2.
44. SMALL a n d COHEN, J.A.G.S., 1932,54, 70. S P E Y E B and KOULEN, Ann., 1924,
802. 438, 34.
XVI
METATHEBAINONE
T H E reduction of thebaine [i] [1-2] and codeinone [n] [3] with stannous
chloride and hot concentrated hydrochloric acid and the catalytic
hydrogenation of thebaine in > 5N hydrochloric acid [4, 24] results
in migration of the carbon end of the basic side-chain from C-13 to
C-14 and production of a phenolic ketone, metathebainone [in]. This
ketone was originally called thebainone and was believed to be struc-
turally related to thebaine, but Schopf and Borkowsky realized that a
migration of the side-chain must have occurred during its production
and suggested the name metathebainone in 1927 [2]; this was finally
generally adopted after the true thebainone-A [iv] had been discovered
[5]. The conditions of the stannous chloride and hydrochloric acid
reduction can be varied so that either [in] or [iv] is the main product [5].
NMe0
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Metathebainone 1 J H , 0 88-90 HaO -419 24 benzene 1-4, 7-8
Metathebainone-MeOH . 115-118 MeOH 1
picrate . . . . . 250-253 2
methiodide . . . . 255-256 1
sodium salt . . . . orange 1
plates
oxime-MeOH . . . . 200-201 MeOH 1
phenylhydrazone notcryst. 1
semicarbazone 227 1
Acetylmetathebainone . 100-101 Et 2 O + 1
petrol
methiodide . . . . 223-225 1
phenylhydrazone 225-226 1
semicarbazone . . . . 249 1
Metathebainone methyl ether . 156 1
methiodide . . . . 256 + 182-5 7 15
Benzylidenemetathebainone . 233 EtOH needles 7, 18
picrate . . . . . D. 194 7
methiodide . . . . 195-197 7,18
Kperonylidenemetathebainone 176 EtOH 7,18
Dianhydro-6-aminopiperonalmeta-
thebainone d ihydrobromide 3H2O 258-260 18
Benzylmetathebainone-A 229 needles 18
sodium salt . . . . orange 18
semicarbazone . . . . 155-160 18
Benzylmetathebainone-B 179 EtOH plates 18
oxime . . . . . 152 EtOH columns 18
semicarbazone . . . . 140-145 18
Metathebainone methine 170-171 MeOH yellow 2
needles
methiodide . . . . 252 acetone 2
oxime . . . . . 210-211 BtOH 2
Metathebainone methyl ether methine 65-66 1
methiodide'BtOH 171-172 BtOH 1
oxime hydrochloride . 271-272 1
semicarbazone -MeOH 107-108 MeOH 1
Metathebainone dihydromethine 2
hydriodide . . . . 258-259 2
Metathebainone methyl ether
dihydromethine . . . . 2
methiodide . . . . 154-155 2
Dihydromctathebainone . 54-55 and MeOH 1
76-78
f + 67-1 25 EtOH \
Dihydrometathebainone . 135-136 dry Bt 2 O prisms (+33-1 25 5% 7
HOAcJ
perchlorate . . . . 245 EtOH 2
methiodide D. 243 + 46-6 25 H1O 1
oxime . . . . . 217-218 EtOH + 104-2 18 10% 2
HOAc
, 232 + 109-8 27 10% 8
semicarbazone . . . . 1 217-218 HOAc
H2O + 7
BtOH
Dihydrometathebainone methyl ether not cryst. 1
/ 260 2
methiodide . . .. \ 245 1. 7
Benzylidenedihydrometathebainone . 100-102 needles 18
Dipiperonylidenedihydrometathe- non-cryst. 7
bainone powder
Piperonylidenedihydrometathe-
bainone methyl ether . c. 156 not cryst. 7
Dihydrometathebainone methine 173-174 BtOH 2
Dihydrometathebainone methyl ether
methine . . . . . oil 2
perchlorate . . . . 193-194 2
Dihydromotalhobainono dihydro-
mothino . . . . . 119-121 2
DlhydromoluMiobulnono mothyl other
diliydrotmiUiliio . . . . oil 2
iuuMilodhli) . . . . 117-118 2
mutlioporalilorato ULS -M-O 18 HOCtone 2
IU47.1 B
242 METATHEBAINONE CH. X V I
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Metathebainol CHCI8 87-88 CHCl3 -45-9 25 EtOH 8
Metathebainol -MeOH 92-93 MeOH -61-2 27 EtOH 8
Metathebainol (anhyd.) . dist. resin 8
hydrochloride EtOAc 162 and BtOAc 8
220
hydriodide-H 2 0 H2O 8
methiodide . . . . 225 EtOH 8
6-acetylmetathehainol 150 EtOAc 8
Diacetylmetathebainol . 140 H8O + 8
MeOH
Dihydrometathebainol . c. 120 8
hydrochloride . . . . + 16-4 30 HVO 8
Anhydrometathebainol . 106-107 MeOH -201-0 25 EtOH 8
Aeetylanhydrometathebainol . 166 McOH 8
Bihydroanhydrometathebainol MoOH 8
Dihydrodesoxymetacodeine-MeOH . 72 MeOH 8
Dihydrodesoxymetacodeine (anhyd). dist. resin -93-8 24 EtOH 8
!Tetrahydi-odesoxymetacodoine amorph. 8
hydriodide . . . . -12-5 28 H,0 8
</i-metathebainone D. 227 -339-5 16 13
semicarbazone . . . . D. > 290 13
Dihydro-0-metathebainone D. 270 needles -71-8 25 13
-1: l'-dimetathebainone. 308-310 EtOH needles -532-6 23 CHCl8 21
methiodide . . . . D. 274 21
l)iacetyl-<*-l: l'-dimetathebainone 272-273 EtOH needles 321-4 20 benzene 21
Totrahydro-o-1: l'-dimetathebainone D. > 300 MeOII prisms -390-6 23 EtOH 21
/3-11 l'-dimetathebainone 235-237 -327-9 7 CHCl8 21
methiodide . . . . D. 274 21
Tetrahydro-P-1: l'-dimetathebainone
-3MeOH 2Q8 MeOH prisms -223-9 24 CHCl8 21
B I B L I O G R A P H Y TO C H A P T E R X V I
1. PSCHOBB, P J ? A M , and HEBBSCHMANN, 13. K O N D O and OOHIAI, Ann., 1929, 470,
Ber., 1905, 38, 3160. 224.
2. SOH6PB and BOBKOWSKY, Ann., 1927, 14. Tn-PENEAU, Bull. Soc. Chim., 1915 (4),
458, 148. 17, 109.
8. K N O B B , Ber., 190S, 3 8 , 3171. 15. K O N D O and SANADA, J, Pharm. Soc.
4. CAIJN, J.O.S., 1933, 1038. Japan, 1927, 549, 126.
5. SOHSI?]? a n d H I B S O H , Ann., 1931, 4 8 9 , 16. S C H O H ? and P E B B E Y , Ann., 1930, 483,
224. 169.
6. K N O B B a n d PSOHOBB, Ber., 1905, 38, 17. BOEIIBINGBB-S5HN, D. R.-P. 833,692
3172. (1929); Prdl. 18, 2870.
7. GULLAND a n d ROBINSON, J.O.S., 1923, 18. GULLAND, J.G.S., 1928, 702.
998. 19. W I E L A N D a n d SMALL, Ann., 1928,
8. SMALL a n d M E I T Z N E E , J.A.G.S., 1933, 467, 17.
5 5 , 4602. 20. GOTO, J. Ghem. Soc. Japan, 1929, 5 0 ,
9. G-ULLAND and ROBINSON, Mem. Proa. 603.
Manchester Lit. Phil. Soc, 1925, 21. andKiTASATO,J.nn., 1930,481,81.
69, 79. 22. K O N D O a n d OOHIAI, J. Pharm. Soc.
10. S a n o M and W I N T E B H A L D E B , Ann., Japan, 1927, 549, 923.
1927, 452, 232. 23. G O T O and KITASATO, Ann., 1930, 481,
IJ. Hojwt, Dissertation, Mtinchen, 1926. 87 note 1.
12. K O N D O a n d OOHIAI, J. Pharm. Soc. 24. a n d SHISHIDO, Bull. Ghem. Soc.
Japan, 1927, 549, 913. Japan, 1935, 10, 597.
XVII
THE THIOCODIDES AND
THI0M0RPHIDES
R E P L A C E M E N T of the chlorine atom of /?-chlorocodide [i] by the
hydroxyl group under suitable conditions gives rise to three isomers
of codeine, namely isocodeine [n], tp- and allo-^-codeine [in] (see Chap.
VIII), but when replacement by the SH group is attempted by heat-
ing jS-chloro- or bromocodide with potassium hydrosulphide simultane-
ous oxidation occurs and the dimolecular bisthiocodide, C36H40O4N2S2,
is obtained. In this base two codeine units are linked by SS,
presumably in the 6:6'-position, as replacement of the halogen atom of
bromo- and /?-chlorocodide by groups other than hydroxyl always
results, in other cases, in appearance of the new substituent at position 6
(see Chapter VIII). Bisthiomorphide, C34H36O4]ST2S2, can be prepared
in the same way from bromomorphide, and gives bisthiocodide on
methylation [I]. Though the simple thiocodeines and thiomorphines
are not known, their S-ethers, the alkylthiocodides and alkylthiomor-
phides, may be prepared by treating the halogenocodides and morphides
with mercaptans under suitable conditions. The ethylthiocodides have
been most extensively studied and are selected for discussion here; the
methylthiocodides and methyl and ethylthiomorphides, as far as their
properties are known, correspond in every way with the ethylthio-
codides.
JS-ETHYLTHIOCODIDE
The early work on this compound was confused by Pschorr's failure
to recognize its phenolic nature. H e noted the alkali-soluble nature of
the methiodide and the production of a mono-acetyl derivative, but
concluded, on account of the apparent insolubility of the parent base in
alkali, t h a t fission of the cyclic ether link occurred during the reactions
of the base with acetic anhydride and methyl iodide [7]. That /3-
ethylthiocodide is indeed a phenol was demonstrated by Morris and
Small [3]; it gives coloured solutions with alcoholic ferric chloride and
readily couples with diazonium salts in alkaline solution to give red
dyes; moreover it is soluble in alkali, though not readily so, being a
very weakly acidic phenol.
/3-Ethylthiocodide [xi] results from a-ethylthiocodide [v] by migration
of a hydrogen atom from C-6 to the oxygen of the cyclic ether with the
introduction of a double bond at C-5:6 [3]. A precisely similar change
occurs when codeine methyl ether is heated with alcoholic sodium eth-
oxide, the product being thebainone-A enol methyl ether [xn] [3, 8].
As isocodeine methyl ether is unaffected by sodium ethoxide [8], it is
suggested t h a t a-ethylthiocodide belongs to the codeine series. /3-
Ethylthiocodide contains two double bonds (it can be catalytically
reduced without loss of sulphur to a tetrahydro-derivative) and its
addition reactions point to the conjugation of these [3].
The hydrolysis of /?-ethylthiocodide affords a sulphur-free ketone [7],
which is identical with thebainone-A [ x m ] [3, 9] despite a statement to
the contrary by Schopf and Hirsch [1O]. The ethyl mercaptan liberated
during the hydrolysis adds to unchanged /3-ethylthiocodide to give
dihydro-y8-diethyldithiocodide [xiv], the product of hydrolysis being an
equimolecular mixture of [xin] and [xiv]. An equivalent mixture of
these two bases, or /3-ethylthiocodide itself, on heating with hydrochloric
acid yields only 8-ethylthiodihydrothebainone [xv], the mercaptan
produced by the hydrolysis of [xiv] adding to the thebainone-A.
These additions and hydrolysos can be realized with the individual
oompounds oonoorned, o,g. othyl mercaptan oan be added to thobai-
246 T H E T H I O C O D I D E S AND T H I 0 M 0 K P H I D E S
none-A to give [xv] ("7]. Addition of ethyl mercaptan to [xv] can also be
accomplished, the product being dihydro-jS-diethyldithiocodide [xiv],
which is converted back to [xv] by acids [3].
The addition of mercaptans to thebainone-A is analogous to the
addition of isoamyl and phenyl mercaptans to a: ^-unsaturated ketones
of the benzalacetone type, which has been reasonably explained as a
1:4-addition process [11-12]. The formation of [xiv] from /?-ethylthio-
codide no doubt occurs by 1:4-addition to the diene system, and from
[XII] by addition of mercaptan to the carbonyl group followed by
elimination of water, or by the condensation of mercaptan with the
enol form of the ketone [3].
_/NMe /NMe
0^^=^ EtS SEt MeS'
[XIII] [XIV] [XV] [XVI]
MeO
HO
EtSH
yNMe /NMe /NMe /NMe
0 ^ \ X " S M e EtS^V^^SMe EtS' MeS^/^SEt
[XVII] [XVIII] [XIX] [XX]
These formulae provide a satisfactory explanation of the results of
Pschorr [7], who hydrolysed /3-methylthiocodide [xvi] to a 'thioketone'
(mothylthiodihydrothebainone) [xvn] which underwent addition of
ethyl mercaptan to give a compound (8-methylthiodihydro-^-ethyl-
thiocodide) [XVIII], isomeric but not identical with the compound
(8-othylthiodihydro-^3-methylthiocodide) [xx] obtained by treating
/3-mothylthiocodide with ethyl mercaptan, b u t identical with t h a t
produced by treating /?-ethylthiocodide [xix] with methyl mercaptan [8].
/3-Ethylthiocodide methiodide is formed when the base is treated with
mothyl iodide in cold chloroform and may be hydrolysed to thebainone-
A methiodide, which results directly when /5-ethylthiocodide is treated
with mothyl iodido in aqueous alcohol. A phenol betaine is obtained b y
tho action of cold sodium hydroxido on the methiodide and is convorted
OH. XVIi THE THIOCODIDES AND THI0M0RPHIDES 247
y - E T H Y L T H I O C O D ID B
This base was reported by Pschorr [2] as a by-product in the pre-
paration of the /3-isomer, and was stated to give, on degradation, a
methine base t h a t could not be isomerized, and was thus believed to
have the SEt group at C-8 and to be a stereoisomer of 8-ethylthioco-
dide. The production of this compound was verified by Morris and Small
[3], who showed that it is in fact /3-ethylthiocodide sulphoxide [xxra]
and t h a t it can be prepared from /3-ethylthiocodide b y shaking this with
oxygen in alcoholic solution.
[3], and i/f-codeinone and i/r-codeine will also suffer addition of mer-
captans [8].
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Refs.
Dihydro-8-diethyldithiocodido . 125-126 EtOAo plates -100-0 25 EtOAc 3
fi-ethylthiocodide methine oil 2
hydriodide 196-197 + 49-0 20 H,0 2
methiodide 193-195 + 39-0 20 HaO 2
8-ethylthio-13-vinyltetrahydro
morphenol methyl ether 97-100 + 689-0 20 EtOH 2
a- (or 8-) etliylthiomorphide D. ISO leaflets 15
/3-ethylthiomorphide D.200-202 MeOH 15
Diacetyl-g-ethylthiomorphide amorph. 15
methiodide BtOH D. 158 EtOH 15
O-desmethylthebainone: see Chap. XV
Ethylthio-O-desmethyldihydro
thehalnone. . . . . D.205-208 needles 15
oxime hydrochloride'H 2 O . cryst. 15
Dihydro-(3-diethylditMomorphide 252d. prisms 15
Disthiocodide . . . . 200 EtOH leaflets 1
methiodide . . . . 258 needles 1
Bisthiomorphide . . . . 201 CHCl8 needles 1
B I B L I O G R A P H Y TO C H A P T E R XVII
1. PSCHOBB, Ber., 1906, 39, 3130. 9. SMALI, a n d MOBBIS, J.A.O.S., 1932,
2. and ROLLETT, Ann., 1910, 373, 54, 2122.
1. 10. SCHOPF and HIBSOH, Ann., 1931, 489,
3. MOBBIS a n d SMALL, J.A.O.S., 1934, 224.
56, 2159. 11. RtJHEMAMT, J.G.S., 1905, 17.
4. OOHIAI a n d K O N D O , J. Pharm. Soc. 12. ibid. 461.
Japan, 1926, 538, 99. 13. RAPOPORT a n d B O N N E S , J.A.O.8.,
5. K O N D O a n d OCHIAI, Ann., 1929, 470, 1951, 7 3 , 2872.
224. 14. LTJTZ and SMALL, ibid., 1934,56, 1741.
6. OOHIAI, J. Pharm. Soc. Japan, 1929, 15. PSCHOBB and H O P P E , Ann., 1910,373,
568, 91. 45.
7. PSCHOKR, Ann., 1910, 373, 15. 16. W E I S S and W E I N E B , J. Org. Ohem.,
8. SMALL and B B O W M N G , J. Org. Ohem., 1949, 14, 194.
1939,3, 618. 17. ibid. 1141.
XVIII
14-H YD ROXYCODEINONE,
14-BR0M0C0DEIN0NE,
AND THEIR DERIVATIVES
THBBAINB-N-OXIDB is obtained when thebaine [i] is heated with
30 per cent, hydrogen peroxide alone [1-2], but when the alkaloid is
heated with 30 per cent, hydrogen peroxide in glacial acetic acid a
different substance, 14-hydroxycodeinone [in], is formed [3-7] (the
maximum yield claimed for this reaction is 76-5 per cent. [7]). In the
same way 14-bromocodeinone [v] results from the treatment of the-
baine with bromine in glacial acetic acid [8]. These two compounds arise
as a result of 1:4-addition of hydrogen peroxide and bromine to the
conjugated diene system in thebaine to give, respectively, [n] and [iv],
which then lose methyl alcohol and methyl bromide respectively, giving
[in] and [v] [9].
STBTJOTXJKB
That 14-hydroxy- and 14-bromocodeinone have the morphine skeleton
intact is demonstrated by the reduction of the latter with ferrous
hydroxide to codeinone [vin] and catalytically to dihydrocodeinone
[8, 13], and its conversion to 14-hydroxycodeinone oxime on treatment
with hydroxylamine [8-9].
14-Hydroxycodeinone was first represented as an a-hydroxy-ketone,
but such a formulation was rejected by Gulland and Robinson [9] on
account of the stability of the base towards alkaline silver and cupric
solutions, and, moreover, the base does not behave as an allylamine in its
reaction with cyanogen bromide [4, 13-16]. A /3-hydroxy-ketone struc-
ture was never seriously considered and is in any case at variance with
the observed difficulty of dehydrating 14-hydroxycodeinone and its
derivatives, but a y-hydroxy-ketone formulation is compatible with all
the experimental facts. 14 Hydroxycodeinone does not show the pro-
perties of a methylene-ketone, but its dihydro-compound does, facts best
explained by postulating the presence of the system COC=CC-OH
in the former [9].
The location of the hydroxyl group at C-14 accounts for the stability
of 14-hydroxycodeinone in acid solution; compounds of the morpho-
thebaine and thebenine types are not formed, as aromatization would
involve elimination of the group at C-14 as well as .migration of the side-
chain from C-13. The stability of 14-hydroxycodeinone and its deriva-
tives to aromatizing dehydration is explained by the absence of a
hydrogen atom on either C-13 or C-8. The loss of C-15 and C-16 during
exhaustive methylation would not in itself render the structure aromatic
and so retention of these two carbon atoms in the nitrogen-free product
is not surprising.
RBDtTCTION
(a) Catalytic hydrogenation of 14-hydroxycodeinone [4, 10, 17-18]
or reduction of this base with sodium hydrosulphite [1, 10, 19] affords
14-hydroxydihydrocodeinone [ix], which is marketed as the drug
'eukodal' [20-22].
(b) Reduction of 14-hydroxycodeinone with zinc-dust and acetic
or formic acid [4, 10, 23], or zinc-dust and copper sulphate solution [23],
yields ']4-hydroxycodeine', which has been tentatively allotted the
striioture [x], though this is vory unlikely in view of the work of Small
and Lutz (BOO bolow).
OH. X V I I I AND THEIR DERIVATIVES 253
(c) Opening of the cyclic ether link occurs when 14-hydroxycodeinone
is reduced with stannous chloride and hydrochloric acid, the product
being 14-hydroxythebainone [xi] [3, 10, 23] (cf. the reduction of
codeinone to thebainone-A). The formation of a substance of the
metathebainone type by migration of the side-chain from C-13 to C-14
is blocked by the presence of a hydroxy! group at the latter position.
CHLOKINATION
Treatment of 14-hydroxydihydrocodeine-B with thionyl chloride
results only in chlorination of the aromatic nucleus (cf. the correspond-
ing reaction with the four dihydrocodeine isomers, Chap. IV), but
treatment with phosphorus pentachloride affords 14-hydroxy-6-
chlorodihydrocodide [xix]. That the hydroxyl group at C-6 is the one
that is replaced by chlorine is revealed by the fact t h a t reduction of
[xix] by sodium amalgam and alcohol is attended by rupture of the
cyclic ether link, giving 14-hydroxydihydrodesoxycodeine-C [xx],
which is readily reduced catalytically to 14-hydroxytetrahydrodesoxy-
codeine [xin]. AU attempts to reduce [xix] to a non-phenolic base, or
to secure elimination of hydrogen chloride with production of a sub-
stance of the desoxycodeine-C type failed [6].
14-Hydroxydihydrocodeine-B on successive treatment with thionyl
chloride and phosphorus pentachloride in either order is converted into
l-chloro-14-hydroxy-6-chlorodihydrocodide. I t is surprising that only
one of the two hydroxyl groups is replaced by halogen, and t h a t this
should be the secondary rather than the tertiary one; the reason for
this may be that the latter is located at a ring juncture, but against this
can be set the fact that neither the bromine of 14-bromocodeinone nor
the similarly placed hydroxyl groups in certain toad poisons are inert
[6].
I n contrast to 14-hydroxydihydrocodeine-B the C-isomer is con-
verted by phosphorus pentachloride to substances containing phos-
phorus. The difference in behaviour of the two isomers is similar to
t h a t of the epimeric pair dihydrocodeine and dihydroisocodeine, and
there is nothing about the chemical or pharmacological properties of the
two isomers incompatible with the view that 14-hydroxydihydrocodeine-
B has the codeine and the C-isomer the isocodeine arrangement of
groups at C-6 [6],
Compounds of the 14-hydroxycodeinone series yield mainly intrac-
table substances on treatment with chlorinating agents. The most
extensively studied of these reactions is that between 14-hydroxy-
codeinone and phosphorus pentachloride, which gives up to 20 per cent,
of crystalline material. The product has been resolved into seven sub-
stances, namely, one monochloro-compound, two dichloro-compounds
(believed to be ketochlorides), three trichloro-compounds (possibly
ketochlorides with a chlorine atom at C-14), and a tetrachloro-compound
[6, 31]. '14-chloroketochloride-A' can be catalytically reduced to
dihydrodesoxycodeine-D [xxi] and tetrahydrodesoxycodeine [ x x n ] so
must have the original skeleton intact [6], The monochloro-compound
is not idontioal with 14-chlorooodeinone [xxirr], which can bo prepared
in 80 per oont. yield by tho action ofiodobonzono diohlorido on tliobaine
256 14-HYDROXYCODEINONE, 14-BROMOCODEINONE OH. xvm
[31]. Neither [ x x m ] nor 14-bromooodeinone can be chlorinated with
phosphorus pentachloride [31].
MeO^/H^ MeO- Y ^ : % MeO v ^ % MeO^./X^-Br
^NMe NMe
HoEMAJfH D E G R A D A T I O N
(a) The alkaline degradation of 14-hydroxycodeinone methiodide
affords 14-hydroxycodeinone methine [xxv] [4, 3], further degradation
of which affords no definite product [4],
(b) Hofmann degradation of 14-hydroxydihydrocodeinone affords
14-hydroxydihydrocodeinone methine [xxvi], further degradation of
which proceeds with elimination of the nitrogen atom and cyclization
of the residue of the side-chain with the hydroxyl group at C-14, the
product being ' dihydrohydroxycodeone' [xxvn] [4, 34]. This may be
reduced to 'tetrahydrohydroxycodeone' [xxvni] [34]. These names are
unsuitable as neither [xxvn] nor [xxvni] contains a hydroxyl group.
-NMe,
MeO MeO'
-NMe,
HO
[XXXIII] [XXXIV] [XXXV] [XXXVI]
(e) Hofmann degradation of 14-hydroxydihydrocodeine-B affords
14-hydroxydih\drocodeine-B methine [xxxv] and 14-hydroxydihydro-
codeine-B dihydromethine [xxxvi] [6].
The only recorded instance of the dehydration of a 14-hydroxy-
codeinone derivative is t h a t recorded by Schopf and Borkowsky, who
claimed to have dehydrated 14-hydroxydihydrothebainone methine to
[XXXVII] [34]. Now [xxxvn] has the structure assigned to thebainone-B
methine obtained by the hydrolysis of dihydrothebaine-</> methiodide
[xxxvin] and /?-dihydrothebaine methine [xxxix] [35], and whereas
thebainone-B methine can be hydrogenated to /3-dihydrothebainone
MeO ^ ^ % MeO^ MeO MeO
HO HO
MISCELLANEOUS REACTIONS
(i) Ozonolysis of 14-hydroxydihydrocodeinone yields 14-hydroxy-
dihydrocodinal [XLI] [36].
(ii) 14-Hydroxycodeinone reacts with cyanogen bromide without
scission of the nitrogen ring to give 14-hydroxycyanonorcodeinone
[XLII] [4], which can be hydrolysed t o 14-hydroxynorcodeinone [37].
Acetyl-14-hydroxydihydrocodeinone reacts similarly with cyanogen
bromide.
(iii) N-nitroso-14-hydroxydihydronorcodeinone [XLIII] is formed
when 14-hydroxydihydrocodeinone is treated with nitrous acid [38].
(iv) 14-Hydroxycodeinone and 14-hydroxydihydrocodeinone are con-
verted t o -N-oxides b y 30 per cent, hydrogen peroxide [4, 39] and 14-
hydroxycodeinone-N-oxide can be sulphonated to two 14-hydroxy-
codeinone-N-oxide sulphonic acids, which m a y be reduced to 14-
hydroxycodeinone sulphonic acid [17] or to 14-hydroxydihydrocodei-
none sulphonic acid [40].
(v) 14-Hydroxydihydrocodeinone oxime sulphonic acid has been
claimed to be formed by the action of sodium hydrosulphite on 14-
hydroxycodeinone followed by conversion to the oxime [40].
CH3
[XLI] [XLII] [XLIII] [XLIV]
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
l-chloro-14-hydroxydihydro-
codeine-B . . . . . oil 6
hydrochloride . . . . 238-239 BtOH -106-0 21 H2O 6
l-chloro-14-hydroxy-6-chloro- 163-5 BtOH prisms -141-0 22 10% 6
dihydroeodide HOAc
14-hydroxy-6-chlorodihydrocodide . 213-5-214 EtOAc 151-0 22 10% 6
HOAc
14-hydroxydihydrodesoxycodeine-C . 137-138 EtjO -19-0 22 10% 6
HOAc
14-hydroxytetrahydrodesoxycodeine
perchlorate . . . . 242-244 H1O -28-0 21 H2O 6
Phosphorus compd. from 14-hydroxy-
dihydrocodeine-C + PCl5 136-139 6
14-hydroxythebainone . D.104-106 Et 2 O 4- 4, 23
EtOH
hydrochloride . . . . D. 305 -68-8 18 H2O 4
mcthiodide . . . . 245 4, 23
dibromide . . . . 258 4,23
oxime . . . . . D. 255 23
Acctyl-14-hydroxythebainone . 197 EtOH 23
mcthiodide . . . . 212-213 23
oxime 216-218 23
14-hydroxydihydrothebainone. 140-145 petrol 4, 23, 34
hydrochloride . . . . D. 310 -52-5 20 H2O 34
hydrochloride 2H1O . 270-272 95% -123-0 25 H2O 6
EtOH
/170-180 H,0 I 4
perchlorate . . . . I D. 270
EtOHJ
methiodide-H 2 O D. 210 4
oxime . . . . . 220-222 4
Acetyl-14-hydroxydihydrothc-
bainone . . . . . 214 EtOH 4
14-hydroxydihydrothebainone
methyl ether . . . . 151-153 34
perchlorate . . . . 134 4
methiodide . . . . 206-208 34
14-hydroxydihydrothebainone 242-243 -81-9 20 d'ii. 4
methine HOAc
hydriodide . . . . C 158 4
14-hydroxydihydrothebainone
methyl ether methine . 131-133 34
methiodide . . . . 209 34
14-hydroxydihydrothebainone 239-240 -45-2 20 d'ii. 4
dihydromethinc HOAc
methiodide . . . . 4
14-hydroxydihydrothobainone
methyl ether dihydromethme 83-85 34
' Tetrahydrohydroxythebaone" 143-144 4
'Methyldihydrohydroxythebaone' . 87-89 34
' Methyltetrahydrohydroxy thebaone' 74-76 34
14-hydroxythebainol 234 CHOl8 prisms 23
hydrobromide . . . . 252-253 23
hydriodide H 2 O 247 H2O 23
picrate . . . . . 204-205 23
N-oxide . . . . . D. 237 23
methyl ether methiodide D. 233 H2O 23
Eormyl-14-hydroxythebainol . 277 23
hydriodide . . . . D. > 305 23
Benzoyl-14-hydroxythebainol . D. 257 23
14-hydroxythebainol methyl ether
methine 195-197 23
hydriodide . . . . 255 23
mothlodide ' . . . . D.239-240 + 141-8 20 H2O 23
N-free product 0,,Hj 0 O 1 188-189 -29-0 19 CHCl3 23
14-hydroxydlhydrocodinal 285d. 36
14-bromocodoinono 3 56-157 8,13
hydrochloride'2U 9 O . 104 8
hydtnbromldO'U.O . 107-108 . -| 8
- - Nn1H1Oi niilu. I)Ii)(IiKiI 11.240 U-11 28
I-nllm-1 i-lmimoiioiloliionu )). 210 Iirlsmn 40
lil-ohlorooottciliioni). >. .. 81
262 U-HYDROXYCODEINONE, 14-BROMOCODEINONE CH. x v m
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Rep.
Acetyl-8:14-dihydroxydihydro-
196 M1O 12
-III1
8:14-dihydroxycodeinone 171 12
chromate . . . . 12
Dehydrothebaine . . . . I
T H E R E A C T I O N OF ^ - C O D E I N E AND
THEBAINE DERIVATIVES WITH
GRIGNARD REAGENTS
T H E cyclic ether link and 6:7-double bond in derivatives of i/r-codeine
[i] and thebaine [n] form a reactive conjugated system capable of
undergoing a reaction with Grignard reagents that involves scission of
the ether bridge and entry of an organic radical into the molecule.
Activation of the 4:5-ether bridge by a 6:7-double bond appears to be
necessary for reaction to occur, as derivatives of codeine [in], ^-codeine,
and thebaine that have no such double bond cannot be made to react
with Grignard reagents. (The reaction between a-chlorocodide [iv] and
methylmagnesium iodide is no exception to this, as in that case the
Grignard reagent functions in a reducing capacity only; see Chap. VIII.)
The reactions may be divided into two types: (a) those giving 'nor-
mal' products, and (6) those giving 'abnormal' products in which a
marked change in the original molecular structure has occurred. Of
these the former only are considered here, the latter being discussed in
Chapter XX.
T H E R E A C T I O N OF D I H Y D K O T H E B A I N E W I T H
METHYLMAGNESIUM H A L I D E S
Methylmagnesium halides readily react with dihydrothebaine [v]
[1-7] when this is slowly introduced into the reaction mixture, giving
mainly the phenolic base methyldihydrothebainone together with
10 per cent, of an isomeric phenol isomethyldihydrothebainone, the
enol ether group of [v] being hydrolysed during the reaction or, more
probably, during the isolation of the products. A more convenient
method of preparation of these bases is by the very vigorous reaction
of methylmagnesium halidos with dihydrocodoinone enol acetato [vi],
which is moi'o easily prepared than dihydrothebaine [8]. It has boon
264 R E A C T I O N OF ^ - C O D E I N E AND T H E B A I N E OH. XIX
T H E R E A C T I O N OE D I H Y D R O T H E B A I N E WITH OTHER
GRIGNARD REAGENTS
(a) The reaction between dihydrothebaine and ethylmagnesium
iodide affords ethyl- and isoethyldihydrothebainone, the former of
which has been converted to ethyldihydrocodeinone and ethyldihydro-
morphinone, reduction of which could not be effected [8].
(6) Dihydrothebaine reacts with t'sopropylmagnesium iodide to give
isopropyldihydrothebainone and dihydromorphinone A6-enol methyl
ether, the latter being formed by the demethylation of dihydrothebaine
by the Grignard reagent. Ring closure of ^opropyldihydrothebainone
to isopropyldihydrocodeinone can be effected as before and the rever'se
ohange can be brought about by the Clemmensen reduction of the
latter. Neither isopropyldihydrocodeinone nor isopropyldihydromor-
phinone can be reduced at the carbonyl group [8].
(c) -Amyl- and benzyldihydrothebainones have been prepared and
these have been converted to the corresponding substituted dihydro-
codeinones and dihydromorphinones [8].
(d) Phenyl- and isophenyldihydrothebainones, which result from the
interaction of dihydrothebaine and phenylmagnesium bromide, can be
converted to phenyldihydrocodeinone and isophenyldihydrocodeinone,
the first of which can be demethylated, when phenyldihydromorphinone
is obtained. Vaouum-distillation of isophenyldihydrothebainone methyl
other mothoohlorido in an attempt to obtain the baso affords a substance
CH. xix DERIVATIVES WITH GBIGNARD REAGENTS 267
R
[XXI] [XXII] [XXIII] [XXIV]
Solvent
for Crystal Specific
Compound m.p. 0C. recrystn. form rotation Temp. Solvent Befs.
Isopropyldihydrothebainone . 217-5- BtOH needles -31-0 23 CHCl2 8
219-5
hydrochloride . . . . 273-275* EtOH rods -18-3 25 H2O 8
hydrobromide . . . . 277- H2O -12-6 24 H2O 8
277-5*
perchlorate . . . . 236-238* BtOH -16-0 25 acetone 8
salicylate . . . . 165-185* EtOH needles -8-9 25 acetone 8
oxime-2H 2 O . . . . 199-201 EtOH + 13-5 25 EtOAc 8
oxime hydrochloride . 213-215* + 43-8 26 H2O 8
1:5-dibromoisopropyldihydro-
thehainone hydrobromide 230-232* EtOH -2-7 24 EtOH 8
M-Amyldihydrothebainone 153-155 acetone -12-8 26 EtOH 8
hydrochloride -H2O 203-205 H,0 + 2-8 24 EtOH 8
hydrobromide . . . . 223- H2O plates + 1-5 25 EtOH 8
224-5*
hydriodide . . . . 238-239* 50% plates -1-4 25 EtOH 8
EtOH
perchlorate -^H2O 235-236* 25% plates -2-1 25 EtOH 8
EtOH
sulphate -H8O . . . . 95-105 H2O rods O 24 EtOH 8
oxime . . . . . 113-115 EtOH plates + 18-6 25 EtOH 8
1-bromo-m-amyldihydrothebainone . 241-242 EtOH rods -30-6 25 EtOH 8
Benzyldihydrothebainone 227-229 EtOH needles -51-6 25 CHCl3 8
hydrochloride . . . . 243-244* EtOH -29-0 25 H2O 8
oxime . . . . . 135-142 benzene + 5-5 25 CHCl3 8
1-bromobenzyldihydrothebainone 230-232* EtOH needles -59-4 23 EtOH 8
Phenyldihydrothebainone 230-232 EtOH -165-9 24 CHCl3 8
perchlorate . . . . 201* 95% -97-6 25 acetone 8
EtOH
methiodide . . . . 245-248* 30% -96-5 25 EtOH 8
EtOH
oxime . . . . . 198-200 EtOH -106-7 24 EtOH 8
Isophenyldihydrothebainone . 213-215 EtOH needles + 34-8 24 CHCl3 8
methiodide . . . . 214-215 EtOAc + O 24 EtOH 8
MeOH
oxime . . . . . 230-232 EtOAc needles -157-0 24 EtOH 8
methyl ether methiodide 264-265* MeOH + + 49-3 24 EtOH 8
EtOAc
methyl ether methochloride 239-243 8
PhenyI-3:4-dimethoxy-6-kcto-
5:6:7:8-tetrahydrophonanthrene ? 227-230 EtOAc plates -130-0 22 benzene 8
Dimethyldihydrothebainone . 199-202 acetone + 3-5 26 EtOH 8
oxime . . . . . C 70-90 petrol 8
Methyldihydrothebainonc methine . 164-165 EtOAc needles + 163-0 20 EtOH 15
methiodide . . . . 246-249 MeOH + 117-0 20 EtOH 15
/somethyldihydrothebainono methine 193 EtOAc + 231-0 20 EtOH 15
methiodide . . . . amorph. 15
Methyl-9:10-dehydrothebenone 183-184 EtOH + 262-0 20 acetone 15
jTsomethyl-9:10-dehydrothebenone . 116-5-117 EtOH + 252-0 20 EtOH 15
Methyldihydrocodeinone. 144-144-5 EtOAc needles -146-9 23 EtOH 1
methiodide . . . . 246-248 EtOAc -74-2 24 H2O 1
1-bromomethyldihydrocodeinone 143-5-145 EtOAc -109-4 24 EtOH 1
Methyldihydrocodeinone enol acetate 191-5- EtOAc -142-9 23 EtOH 1
194-5
Methyldihydrocodeinone glyoxalic
acid hydrochloride cryst. 1
jsomethyldihydrocodeinone 144-145 EtOAc -179-4 24 EtOH 1
hydrochloride . . . . 191-193* EtOH needles -122-1 21 H2O 8
hydriodide H2O 209-210 EtOH needles -102-1 21 H2O 8
Jsomethyldihydrocodeinone enol
acetate . . . . . 123-124 EtOAc -250-3 24 EtOH 1
Jsomethyldihydrocodeinone glyoxalic
acid . . . . . . oil 1
Ethyldihydroeodoinono . 163-164 EtOAc needles -100-9 25 EtOH 8
mothiodldo-JII.O 265-257* EtOH -48-8 21 H2O 8
1-bromoothyldlhydrocodoinone oil 8
Ethyldlhydrooodulnono onol aootato , 129-130 50% -124-1 25 EtOH 8
UtOU
lBopropyldlhydroundnlnouo L75-I77 JOtOU noodlos -110-5 26 JSlOH 8
hydrobromldo . . . . liOIMiOft* JI1O noodlos -58-3 2D 11,0 8
* In ovaouatod tube.
270 R E A C T I O N OF ^ - C O D E I N E AND T H E B A I N E
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Isopropyldihydrocodeinone hydrio-
dide-H 2 0 196-198* H2O rods -67-2 25 EtOH 8
methiodide . . . . 274-275* H2O + -66-0 25 acetone 8
BtOH
oxime . . . . . 224-226* EtOAc lozenges -25-0 23 BtOH 8
1-bromoisopropyldihydrocodeinone . 164-167 EtOAe -79-0 24 acetone 8
n-Amyldihydrocodeinone 153-155 EtOAo+ -9-3 26 EtOH 8
petrol
picrate . . . . . 174-177 EtOH plates -52-8 24 acetone 8
salicylate . . . . . EtOH needles 8
styphnate-fH 2 0 142-145 EtOH plates -45-4 25 acetone 8
l-bromo--amyldihydrocodeinone . 143-145 EtOH -76-7 24 EtOH 8
1121-123
oxime-JH 2 O . . . . J and MeOH -29-7 24 EtOH 8
1170-174
Benzyldihydrocodeinone oil -114-3 25 CHOl2 8
1-bromobenzyldihydrocodeinone 167-168 EtOH needles -101-4 23 EtOH 8
Phenyldihydrocodeinone 149-151 BtOAc + -166-2 24 EtOH 8
petrol
1-bromophenyldihydrocodeinone oil 8
Methyldihydrocodeine 'HjO 98-102 50% -84-8 24 BtOH 1
BtOH
Methyldihydrocodeine (anhyd.) 85-88 subl. 1
hydrochloride . . . . 286-287* EtOH -64-5 23 H2O 1
methiodide . . . . 269-271* EtOH -47-9 24 H2O 1
Isomethyldihydrocodeine JH 2 O 103-104 EtOH -126-9 21 EtOH 8
salicylate . . . . . 235-237* EtOH -87-3 21 EtOH 8
methiodide . . . . 252-254 75% -56-8 21 H2O 8
EtOH
Methyldihydromorphinone 243-245* EtOH needles -140-7 24 EtOH 1
hydrochloride . . . . 315-318* EtOH -104-8 24 H2O 1
Bthyldihydromorphinone 213-214* EtOH -103-5 25 EtOH 8
hydriodide . . . . 285-286* EtOH needles -49-1 22 H2O 8
methiodide JHjO 263-265* EtOH -42-2 22 H2O 8
Isopropyldihydromorphinone . 236-238 EtOH -107-5 26 BtOH 8
hydrochloride H2O 340-341* acetone prisms -64-2 25 H2O 8
hydrobromide . . . . 215-220* H2O needles -56-4 23 H2O 8
hydriodide H2O 199-201* H2O -61-5 25 acetone 8
porchlorate IJH 2 O 168-170* 33% plates -69-0 25 EtOH 8
EtOH
n-Amyldihydromorphinone JH 2 O . 113-116 EtOAc -97-3 25 EtOH 8
hydrochloride . . . . 322-325* H2O plates -63-9 25 H2O 8
hydrobromide-H 2 O . 189-190* EtOH prisms -66-0 25 EtOH 8,
hydriodide-H 2 O 182-184* EtOH needles -59-8 25 EtOH 8
Bonzyldihydromorphinone 166-167-5 EtOH prisms -439-0 24 CHCl, 8
hydrochloride-H 2 O . 241-242* EtOH prisms -100-6 24 H2O 8
Plumyldihydromorphinone 278-280* EtOH prisms -164-5 24 acetone 8
hydrochloride . . . . 334-337* 90% needles -126-9 24 H2O 8
EtOH
hydrobromide . . . . 281-284* 90% rods -97-4 25 acetone 8
EtOH
hydriodide . . . . 273-276* 90% prisms -95-1 25 acetone 8
EtOH
Dihydromorphinone A"-enol methyl 233-235 EtOH rods and -206-5 24 EtOH 8
other needles
hydrochloride . . . . 309-310* H2O prisms -180-6 25 H2O 8
hydriodide . . . . 274-275* H2O -140-5 25 H3O 8
bonzoate 229-230 EtOH rods -150-7 25 EtOH 8
salicylate . . . . 268-270* H2O + needles -130-8 25 acetone 8
EtOH
mothlodide-HjO 259-261* MeOH needles -123-6 25 acetone 8
Mothyldihydromorphine 206-207 EtOAc -92-9 24 BtOH 1
hydrochloride . . . . 316-317* EtOH -65-7 23 H2O 1
hydriodide . . . . 289-291* EtOH -50-5 23 H2O 1
Motliyldihydrodosoxycodelno-O 145-146 MeOH + 69-7 25 BtOH 19
hydrobromldo . . . . 245-246 H2O plates + 61-5 23 CHCl3 19
hydriodide . . . . 155-158 H2O + 51-9 23 CHCl, 19
mutlilodldo . . . . 289 acetone + 28-8 25 CHCl, 19
MoUiylUitrfthydrodosoxyoodoino 128-129 MoOH -47-8 25 EtOH 19
liydroohlorlilo . . . . 240-5 aootono noodles -28-1 25 OHOl, 19
* In evacuated tube.
OH.xxx DERIVATIVES WITH GRIGNABD REAGENTS 271
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Refs.
Methyltetrahydrodesoxy codeine
hydrobromide . . . . 248-249 HjO -21-9 22 CHCl8 19
methiodide . . . . 254-255 EtOH -34-9 25 CHCl3 19
a-Ethyldihydrodesoxycodeine-C 156-164 acetone -184-0 22 CHCIs 19
hydriodide . . . . 205-210 50% -123-2 23 EtOH 19
BtOH
perchlorate . . . . 187-200 50% prisms -134-7 26 EtOH 19
BtOH
methiodide . . . . 210-215 H3O -111-4 26 BtOH 19
i8-Ethyldihydrodesoxycodeine-C oil 19
a-Ethyltetrahydrodesoxycodeine 168-5-169 subl. -54-8 23 CHCl1 19
hydriodide . . . . 234 20% -2-9 24 CHCl, 19
MeOH
0-EthyItetrahydrodesoxycodeine 148-153 acetone -37-6 26 CHCl3 19
Ca/ctohexyldihydrodesoxycodeine-C . 131-5- MeOH+ -51-0 26 CHCl3 19
132-5 isoPrjO
perchlorate . . . . 250-251 -26-3 25 CHCl3 19
Cj/efohexyltetrahydrodesoxycodeine . 193-193-5 MeOH -14-2 25 CHCl3 19
hydriodide . . . . 235-236 + 14-8 23 CHCl3 19
Phenyldihydrodesoxycodoine . 184-5- BtOAc + 129-3 24 CHCl3 19
185-5
picrate-H 3 0 . . . . c. 115 MeOH 19
picrate (anhyd.) 129-132 + 69-5 20 CHCl. 19
- benzoate . . . . . 203-204 Et 3 O + + 82-1 24 BtOH 19
EtOH
methiodide . . . . 257-5-258 EtOH flakes + 105-0 25 EtOH 19
Octahydrophenyldihydrodesoxy-
codeine . . . . . 132-134 -48-4 24 CHCl3 19
perchlorate . . . . 255-256 -16-7 26 BtOH 19
methiodide . . . . 250 BtOH -28-0 25 CHCl1 19
Phenyltetrahydrodosoxycodeine 218-220 H2O + + 16-1 26 CHCl3 19
MeOH
Methyldihydro-^-codeine methyl
ether . . . . . 182-5-183 EtOAc + 121-0 23 EtOH 8
hydrochloride . . . . 247-251* EtOH needles + 125-9 25 H1O 8
hydriodide . . . . 256-257* EtOH needles + 91-5 25 EtOH 8
perchlorate . . . . 285-287* EtOH + 103-1 23 EtOH 8
methiodide . . . . 273-276* BtOH needles + 98-1 25 EtOH 8
By-product in preparation of above
in isopropyl ether 132-132-5 BtOAc -57-4 25 EtOH 8
* In evacuated tube.
THE PHENYLDIHYDROTHEBAINES
The reaction between thebaine and phenylmagnesium bromide was
first investigated by Ereund [1-2], who obtained in this way a phenolic
base, the composition of which was C25H27O3N = thebaine+C 6 H 6 ; the
base was accordingly named phenyldihydrothebaine. The peculiar
properties of this compound at once became evident. I t was found to be
strongly resistant to hydrogenation; to be so stable in concentrated
acids t h a t demethylation could be accomplished without structural
change, though no hydrolysis of the 'enol-ether' methoxyl group could
be effected. Furthermore, exhaustive methylation resulted in loss of
trimethylamine only, and retention of the residue of the basic side-chain
as a vinyl group, a reaction without parallel in a compound of the mor-
phine series in a comparable state of unsaturation. These facts Ted
Ereund to postulate some unlikely formulae for thebaine. The reduction
of phenyldihydrothebaine was subsequently accomplished, but was
found to involve reductive scission of the nitrogen-containing ring, the
product being a secondary amine, phenyltetrahydrothebaimine [3].
The problem was investigated by Small, Sargent, and Bralley [4],
who, following work by Small and Fry on the methyldihydrothebaines
(prepared by the interaction of thebaine and methylmagnesium iodide
[5], see below), resolved the phenyldihydrothebaine obtained from the
Grignard reaction into two enantiomorphic bases, designated (+)--
and (+)-S-phenyldihydrothebaine, in the ratio of approximately 10:1.
That both are phenolic as well as basic was shown by their solubility
in alkalis and ready coupling with diazonium salts. As with the corre-
sponding methyldihydrothebaines, these bases were made to undergo
isomerization by slow distillation in a high vacuum, or by heating in
an ovaouated sealed tube at 200 C , under which conditions (+)-a-
phonyldihydrothobaino was recovered 75 per oent. unohanged together
CH. X X THE PHENYLDIHYDROTHEBAINES 273
with 16 per cent, of a new isomer termed by Small ()-S, identical with
the (-j-)-S form except for the opposite sign of optical rotation. A
fourth isomer, ()-a, equal and opposite in optical rotatory power to
the ( + ) - form, was prepared in the same way from (+)-S-phenyldi-
hydrothebaine. The existence of two centres of dissymmetry in the
phenyldihydrothebaine molecule is thus evident; the equilibria reached
from either side favour the a-forms [4].
Small clearly recognized these changes as partial racemizations, but
appears to think it possible t h a t a number of asymmetric centres can
be inverted in a single step, for he calls the optical antipode of ( + ) - a
(-)-. I t is preferable to term it ()-, however, for then (-(-), (), a,
and S can be taken as symbols representing left-hand or right-hand at
two sources of dissymmetry and the partial racemization of ( + ) - a by
heat then gives ()-a [6, 7].
Examination of the products of exhaustive methylation of the
phenyldihydrothebaines demonstrated convincingly t h a t the difference
between the a and S series is due solely to asymmetry about a carbon
atom joined directly to the nitrogen atom, the difference between the
two series vanishing when the nitrogen atom is eliminated from the
molecule. The ( + ) : ( ) isomerism, however, persisted in the nitrogen-
free products.
Any satisfactory formula for phenyldihydrothebaine must give an
adequate explanation of the following:
(a) The resistance of the base to hydrogenation [1, 4],
(6) The stability of the base in acid solution [1, 4].
(c) The retention of the vinyl group during exhaustive methyla-
tion [4].
(d) Demethylation of phenyldihydrothebaine gives norphenyl-
dihydrothebaine [1], which exhibits the properties of a trihydric
phenol and can be methylated to phenyldihydrothebaine methyl
ether [4, 8].
(e) Partial racemization about an asymmetric carbon atom attached
directly to the nitrogen during the entry of the phenyl group [4].
I n spite of (a), (b), (c), and (d) Small, Sargent, and Bralley rejected
the obvious explanation that the near-aromatic nucleus of thebaine,
which bears the hydrolysable methoxyl group, has become fully
aromatic in phenyldihydrothebaine. If this ring is made aromatic, it
was claimed, not only can no place be found for two hydrogen atoms,
b u t the optical activity of phenyltetrahydrothebaimine cannot be
explained [4-5]. Comparison was made between the ultra-violet
absorption spectra of the phenyl- and methyl-dihydrothebaines and
that of the most olosely related thebaine derivative in which it is known
t h a t no doep-soated structural change has ocourred, namely dihydro-
thobaino-^ [i] (at that time bolioved to be [n]). These oompounds show
M17.1 X
274 P H B N Y L D I H Y D B O T H E B A I N E S AND COMPOUNDS OH. xx
maxima and minima at almost identical wave-lengths, whereas the
absorption spectra of metathebainone [in] and apocodeine [iv], in
which rearrangement has taken place are widely different (Fig. 10).
Moreover, the absorption spectra of phenyldihydrothebaine methine
and jS-codeimethine [v] are closely similar, whilst that of a-codeimethine
[vi], with the aliphatic double bond at C-7:8 out of conjugation, differs
markedly (Fig. 11). The spectrum of phenyldihydrothebaine gave no
indication of the appearance of a new aromatic nucleus in conjugation
with that already present in thebaine, and Small regarded this as un-
surmountable evidence against the postulate of aromatization of ring C
in phenyldihydrothebaine [4].
In this way Small, Sargent, and Bralley advanced the structure [vn]
for phenyldihydrothebaine, although it fails to explain any of the
anomalous properties of the base, and at the same time questioned the
validity of the Gulland and Robinson formulae for morphine and
thebaine [4]. It is difficult to see how [vn] could arise from thebaine,
as a 1:4-addition of the Grignard reagent to the allylic ether would
give [vin]; moreover, [vn] is not in agreement with the ultra-violet
spectrum of phenyldihydrothebaine, which is not styrenoid. The origi-
nal paper [4] must be consulted for the formulae of degradation products
based on [vn], as here all degradations are interpreted on the basis of
the structure [xi] for phenyldihydrothebaine proved by Bentley and
Robinson [6-7, 9-10].
The one inescapable conclusion to be deduced from the properties of
phenyldihydrothebaine outlined above is that in this base the near-
aromatio nucleus of thobaino has bocomo fully aromatic, and other
OH. X X THE PHENYLDIHYDROTHEBAINBS 275
... / \
N. Vo \ \
4O o ,
\ W \ I
1 / \. \O
D
O
2 ^wyA
K p
/ \ V
(O
O \ VA /A \
O
-"35 \ H\ O / \ i O
' 1
i /"'\ \ \
\ /' \
30
i
i
i
i
Mi-
/' i
i / M
, \ / Al
2-5- I \J I :r I
4O
2
LO
Q
'3-5
[i-CODEIMETHINE(V)
3O
ex-CO D EIMETHINE (Vl)
25
25OO 3000 35OO
WAVELENGTH A
Eio. 11.
The structure first suggested on the basis of the above reasoning was
[rx], which explained all the data then known (1945) except the forma-
tion of two isomers during the entry of the phenyl group. This view was
not maintained, however, as phenyldihydrothebaine does not show
diphenyl bands in its ultra-violet absorption spectrum and [ix] contains
an unrestricted diphenyl system.
DEGRADATION
Elucidation of the degradations of phenyldihydrothebaine on the
basis of [xi] is simple. Small, Sargent, and Bralley [4] studied the
degradations of the four enantiomorphs, though some of the degradation
products had previously been prepared by Freund [1], who worked
with the mixture of (-f)-a and (-f)-S forms obtained directly from the
Grignard reaction.
Although they are fairly resistant to degradation all the phenyldi-
hydrothebaines, with the exception of the rare ()-a-isomer, have been
converted to nitrogen-free substances. In the first stage of exhaustive
methylation they undergo degradation in two ways, giving methines
[xvi] and isomethines [xvn], the latter predominating in each case; in
fact the normal methine was only isolated during the degradation of the
(-f)-a-isomer.
The normal methine, which can be hydrogenated to the dihydro-
mothino [xvin], is unaffected by boiling with concentrated hydrochloric
aoid, whilst the vinyl group of the isometbine [xvu] oan bo oyolized
OH. x x THEPHENYLDIHYDROTHEBAINES 279
REDUCTION
Being a benzylamine, phenyldihydrothebaine can be reduced cataly-
tically [3-4], but not with sodium and liquid ammonia [18], to the
secondary amine phenyltetrahydrothebaimine [xxvn], which on treat-
ment with nitrous acid gives an N-nitroso-compound and on treat-
ment with phosgene yields bis-[phenyltetrahydrothebaimine]-urea [3].
Phenyltetrahydrothebaimine-N-methomethiodide is identical with
phenyldihydrothebaine dihydromethine methiodide, showing that
fission of the ring has occurred between the nitrogen atom and the
carbon atom carrying the phenyl group. This is confirmed by the fact
that both (-|-)-a and (-|-)-8-phenyldihydrothebaino give tho same
(-|~ )-phonyltotrahydrothobaimin [4], Phenyltotrahydrothobaimino-
OH. X X THE PHENYLDIHYDROTHEBAINES 281
N~methomethiodide can be degraded to 'vinylphenyltetrahydrothe-
baol' [XXVIII]. The parent base may be reduced over platinum oxide
to give hexahydrophenyltetrahydrothebaimine [xxrx], presumably
with reduction of the phenyl group; the same base can be obtained
directly from phenyldihydrothebaine and can be degraded to a nitrogen-
free substance [xxx] [4]. An attempt to verify the reduction of the
phenyl group by the preparation of cycfohexyldihydrothebaine failed,
as, though a reaction occurred between thebaine and cycfohexylmag-
nesium bromide, no definite compound could be isolated [4]. Cyclization
of [xxx] should give [xxin].
HALOGBNATION
Phenyldihydrothebaine on treatment with hydrochloric acid and
hydrogen peroxide is converted into a dichloro-compound that has been
degraded to a methine base and nitrogen-free product ('dichlorophenyl-
dihydrothebenol') [3]. IYeund and Speyer regarded this as involving
addition of chlorine to a double bond [3], but the analytical data of
all the derivatives are equally compatible with formulae containing
two hydrogen atoms fewer than those given and it is clear t h a t the
chlorine atoms have entered the guiacol or anisole nucleus or both
nuclei [1O]. The reaction with bromine presumably takes a similar
course yielding dibromophenyldihydrothebaine. This is reported to
undergo electrolytic reduction with the production of 'phenyltetra-
hydrothebaine' [3], which is very probably ( + )-a-phenyldihydrothe-
baine; the melting-points of the methiodides differ by only one degree
[10]. I t is most likely that the small amount of (-)-)-S-isomer originally
present would be eliminated during this cycle of reactions.
Though phenyldihydrothebaine is a benzylamine its acetyl ester
appears to react with cyanogen bromide without scission of the nitrogen-
containing ring, possibly giving [XXXII] [3]. The reaotion between
phonyldihydrothobaine and 30 per cent, hydrogon poroxido in boiling
282 P H E N Y L D I H Y D R O T H E B A I N E S AND COMPOUNDS OH. XX
alkaline solution affords a dibasic acid, phenyldihydrothebainic acid
C24H25O5N [3], for which the structure [xxxni] is now suggested [1O].
THE METHYLDIHYDROTHEBAINES
Methyldihydrothebaine, analogous to phenyldihydrothebaine, results
from the interaction of thebaine and methylmagnesium iodide, and can
be separated into a and S isomers in the ratio of about 2:1. The a-
compound isomerizes to the S to the extent of about 10 per cent, on
heating for twenty-four hours on the water-bath. Two other isomers,
t] and u>, are known, and these are the optical antipodes of the S and a
isomers respectively. In this series the a and ij isomers form a mole-
cular compound on mixing as do also the 8 and <x> isomers. On heating
in a sealed tube a-methyldihydrothebaine gives 20 per cent, a, 75 per
cent, aij-molecular compound, and 4 per cent, a: co-racemate. Under
similar conditions -methyldihydrothebaine gives mainly Sw-molecular
compound and a small amount of a.: co-racemate. That the a, and rj
isomers are in equilibrium is shown by the conversion of the ^-isomer to
the ^-molecular compound on heating in a sealed tube. A small
amount of the to-isomer perchlorate is obtained by heating 17-methyldi-
hydrothebaine perchlorate. The methyldihydrothebaines form three
racemates, namely a: co, S: ij, and acq: Sw. The molecular compounds may
be separated into their constituent isomers by recrystallization of the
hydrochlorides and perchlorates [5].
All four isomeric methyldihydrothebaines can be degraded to iso-
methines [xvn, <j> = CH3], but the acetyl esters of the a, S, and 17
isomers split preferentially in the normal way giving methines [xvi,
<$> = CH3] on dry distillation of the methohydroxides. All the methines
and isomethines degrade to the same nitrogen-free product 'vinyldi-
hydromethylthebaol' [xxiv, <j> = CH3] [5], in which the unsaturated
groups are presumably too small to restrict free rotation of the phenyl
nuclei, as no convincing evidence has been produced to show that this
compound has ever been obtained in an optically active form. (The low
rotatory power of the liquid product of degradation of 8-methyldihydro-
thebaine methyl ether methine [5] can be explained by assuming re-
generation of a quantity of methine base by loss of methanol from the
mothohydroxi do.)
OH. X X THE METHYLDIHYDROTHEBAINBS 283
The vinyl group of the tsomethine may be cyclized with the phenolic
hydroxyl group by boiling in hydrochloric acid, the product being
'methyl-9-dimethylamino-6~methoxythebendiene' [xxxiv], which, un-
like the t'somethine, is non-phenolic and indifferent to catalytic hydro-
genation. With the and t\ isomethines intermediate 8 and i\-
dihydrohydroxymethyldihydrothebaine isomethines [xxxv] may be
isolated if the cyclization is attempted with partially hydrolysed acetyl
chloride; more vigorous treatment with acetylchloride completes the
cyclization to [xxxiv]. Degradation of the cyclized isomethines [xxxiv]
affords two isomeric ' 6-methoxymethylthebentrienes' [xxxvi] [5],
8 'CH2-CH-Me
IkNMe I 0 We
H 2 -CH 3 CH2-CH2
OH
[XXXVII] [XXXVIII] [XXXIX]
Solvent
for Crystal Specific
0
Compound m.p. C recrystn. form rotation Temp. Solvent Refs.
8: ij-racemio methyldihydrothebaine
methine salicylate 190-195 0-0 25 EtOH 5
Dihydrohydroxy-a-methyldihydro-
thebaine isomethine [xxxv] 163-165 BtOAc + 25-0 20 EtOH 5
Dihydrohydroxy-jj-methyldihydro-
thebaine isomethine [XXXV] 5
racemate with 5-isomer 167-168-5 0-0 25 EtOH 5
a-methyldihydrothebaine dihydroiso-
methine . . . . . oil 5
salicylate . . . . 165-167 -47-7 25 EtOH 5
8-methyIdihydrothebaine dihydroiso-
methine . . . . . oil 5
salicylate . . . . . 182-5- +12-8 20 EtOH 5
184-5
a-methyl-9-dimethylamino-6- 76-5-78 H2O + -82-0 22 EtOH 5
methoxythebendiene [xxxtv] EtOH
methiodide BtOH 115-117 BtOH -51-0 25 BtOH 5
methiodide (anhyd.) . 207 BtOAc + 5
EtOH
S-methyl-9-dimethylamino-6- 101-5-103 EtOH + + 33-0 23 BtOH 5
methoxythebendiene [xxxiv] H2O
methiodide JH 2 O c. 155 and EtOH -13-0 25 EtOH 5
207-208
racemate with 11-isomer 110-112 EtOH 0-0 25 BtOH 5
Vinyldihydromethylthebaol [xxrv,
<t> = CH3] 103-105-5 BtOH 0-0 25 EtOH 5
(+)-6-methoxymethylthebentriene 99-101 H2O + + 9-0 22 EtOH 5
[xxxvi] BtOH
( )-6-methoxymethylthebentriene
[XXXTI] 56-59-5 EtOH -5-0 29 BtOH 5
racemate of ( + ) () isomers 91-5-93-5 H 2 O + 0-0 5
BtOH
Product of oxidation of vinyldihydro-
methylthebaol methyl ether. 191-193 0-0 5
Benzyldihydrothebaine . amorph. 2
powder
Mothyldihydro-^-codeinone 213-214-5 iso PrOH 17
BIBLIOGRAPHY TO CHAPTER X X
1. EBETJND, Ber., 1905, 3 8 , 3234. 12. O'SHATJGHNESSY andRODEBTJSH,ibid.,
2. D.M.-P. 181,510 (1907); FrM. 8, 1940, 6 2 , 2906.
1171. 13. F I E S E R a n d F I E S E R , Natural Products
3. a n d S P B Y E B , Ber., 1916,49,1287. Related to Phenanthrene (Am. Chem.
4. SMALL, SARGENT, a n d BEAXLEY, J. Soc. Monographs, ser. 70, New
Org. GMm., 1947, 12, 847. York, 1949).
5. a n d F R Y , ibid., 1939, 3 , 509. 14. TII 1 FENEAXJ, Bull. Soc. Ghim., 1915 (4),
6. ROBINSON, Proc. Boy. Soc, 1947, 17, 109.
1 3 5 B, v-xix. 15. W I E L A N D a n d SMALL, Ann., 1928, 4 6 7 ,
7. Nature, 1947, 160, 815. 17.
8. H O B K , Dissertation, Friedburgh, 1926. 16. SCHMID a n d K A R B E E , HeIv. OMm.
9. B E N T L E Y and ROBINSON, Experientia, Acta, 1950, 33, 863.
1950, 6, 353. 17. L U T Z a n d SMALL, J.A.O.8., 1935, 57,
10. J.CS., 1952, 947. 2651.
11. P I C K E T , WALTES, and FRANCE, 18. B B N T L E Y a n d THOMAS, unpublished
J.A.O.S., 1936, 5 8 , 2296. results.
XXI
THE DIELS-ALDER REACTIONS OF
THEBAINE; FLAVOTHEBAONE
THE DIELS-ALDER R E A C T I O N S OF THEBAINE
I N the Diels-Alder reaction dienophiles such as benzoquinone and
maleic anhydride add readily to a conjugated diene only when the two
ethylenic double bonds are in an open chain or in a ring in which there
is no steric hindrance. The latter condition is fulfilled in thebaine [i],
which would therefore be expected to undergo facile addition of dieno-
philes. Such a reaction was first reported by Sandermann, who noted
that addition of maleic anhydride, p-benzoquinone, and 1:4-naphtho-
quinone occurs slowly in the cold and rapidly on heating [I]. These
reactions have since been more extensively studied by Schopf, von
Gottberg, and Petri [2] and by the author and his co-workers [3, 4].
Thebaine [i] reacts with maleic anhydride in hot benzene solution to
give 'thebaine-maleic anhydride' [II] [1, 2], which on heating with
potassium hydroxide is converted to the dipotassium salt [in,
R 1 = R 2 = K ] . The latter on treatment with the anhydride affords
the monopotassium salt [in, R 1 = H, R 2 = K ?]. The diethyl ester
[in, R 1 = R 2 = Et] is obtained by the action of ethyl alcohol and hydro-
gen chloride on the anhydride or of ethyl iodide on the dipotassium
salt [2].
MeO
MeO
MeO
-NMe
MeO
Medy dooEt
COOEt
LVI]
0417.1
290 T H E D I E L S - A L D E R R E A C T I O N S OF T H E B A I N E OH. xxi
Schopf [2] reported t h a t neither the anhydride nor the ester could be
reduced, but the latter has since been reduced catalytically to ethyl
dihydro-(thebaine-maleate) [iv] and with lithium aluminium hydride
to the diol [v] [3]. An attempt to prepare the isomeric ester [vi] from
fumaryl chloride is in progress [3].
I t is evident from the inspection of models that the addition of
maleic anhydride to thebaine could give rise to four possible forms of the
adduct (shown in the part-formulae [vn], [vni], [ix], and [x]) according
as the anhydride adds across the 6:14-positions on the same side ([vn]
and [vni]) of ring C as, or on the opposite side ([ix], [x]) of ring C to,
the ethanamine side-chain, each mode of addition theoretically giving
two isomers according to whether the anhydride ring in the product is
on the same side of the new ring as the ethylene bridge ([vn] and [x]) or
on the opposite side ([vni] and [ix]). On steric grounds Schopf allots
the structure [n], i.e. the modification represented by [vni], to the
adduct [2].
NMe
s-
MeO MeO 0^> MeO
CH2-OH
[XII] [XIV] [XV]
[XXII] [XXIII]
FLAVOTHEBAONE
When 'thebaine-hydroquinone' is heated with glacial acetic acid
and concentrated hydrochloric acid [2, 4] or with 50 per cent, sulphuric
acid [4] profound rearrangement of the molecule occurs, and a new
base, 'fiavothebaone', is obtained.
Fiavothebaone was assigned the formula C2IH23O5N by Schopf, von
Gottberg, and Petri [2]. The base is yellow in colour and dissolves in
alkali to give a deep red solution. It contains three phenolic groups,
two of which are present in 'thebaine-hydroquinone', as 'thebaine-
hydroquinone' dimethyl ether can be converted to fiavothebaone
dimethyl ether; fiavothebaone methyl ether can be prepared from
'thebaine-hydroquinone' methyl ether. Fiavothebaone is an a:/3-
unsaturated ketone, as is shown by the formation of an oxime and of an
oxime containing a second molecule of hydroxylamine by addition to
the double bond, and by the reduction of fiavothebaone to dihydro-
flavothebaone with sodium amalgam. The base was shown to contain
only one reducible double bond [2].
No crystalline product is obtained when fiavothebaone is oxidized
with hydrogen peroxide, ozone, or other reagents. The trimethyl ether
can be converted to a N-oxide on oxidation with perbenzoic acid; the
N-oxide is reduced to the parent base by sulphurous acid. The trimethyl
ether can be brominated to a dibromo-derivative [2].
The Beckmann transformation of fiavothebaone trimethyl ether
oxime yields an isoxime containing four methoxyl groups, which on
treatment with methanol and hydrochloric acid yields a substance with
one additional methoxyl. Both the isoxime and the methyl-derivative
remain unchanged on heating with methanolic potassium hydroxide
for seven hours [2],
A mothino baso is obtained by the alkalino degradation of flavothe-
baono trimothyl ethor methiodido [2].
294 THE DIELS-ALDEK R E A C T I O N S OE T H E B A I N E OH. XXI
STRUCTURE
The structure of fiavothebaone has been arrived at as a result of the
consideration of the mechanism of the thebaine * morphothebaine
rearrangement, which leads to two formulae for the rearranged sub-
stance, one of which has been shown to be untenable.
Two mechanisms have been suggested for the thebaine > morpho-
thebaine rearrangement (see Chap. X X I I I ) ; these are briefly as follows.
(a) Attack of the cyclic ether oxygen by a proton and demethylation
of the 6-methoxyl group, followed by the electron-shifts a, b, c, d; loss
of a proton from the 6-hydroxyl group followed by the electron-shifts
e, / giving the ketone [xxx] (formulae [xxvin], [xxix], and [xxx]),
which then undergoes isomerization to morphothebaine [xxxi].
(6) Attack of the cyclic ether oxygen by a proton and demethylation
of the 6-methoxyl group to give the carbonium ion [XXXII], isomeriza-
tion of which by the electron-shift m gives [xxxin]. The side-chain of
fxxxni] now moves across the it orbitals to position 8, where a proton
is lost and morphothebaine is formed.
NMc
HON
OH
MeO
[XLIX]
4-5
%
- THEBAINE HYDROOUINONE" (XVII)
4O
O
2
CO
ID
Q
'3-5
3O
THEBAINE- QUINONE(XVI)
2-5
2000 25OO 3000 35OO
WAVELENGTH A
Fro. 12.
O-DESMETHYLFLAVOTHEBAONE IN METHANOL
O-DESMETHYLFLAVOTHEBAONE IN ALCOHOLIC KOH
2': 3-DIMETHOXYBENZYLIDENE -2:5-DIMETHOXYACETOPHENONE
(XXXVILR = Me)
3O
2000 25OO 3000 35OO 4000
WAVELENGTH A
Fio. 13.
45
-, METATHEBAINONE
4O
Q
3-5
FLAVOTHEBAONE
3Q-
20OO 25OO 30OO 3500 4000
WAVELENGTH A
ta. U.
300 THEDIELS-ALDEBBEACTIONSOFTHEBAINE CH. XXI
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
FlavothebaonetrimethyletherlJ-oxide 200-202 2
N-oxide hydrochloride 312d. 2
oxime . . . . . 258 EtOH 2
oxime hydrochloride 2J-H2O 271-272 H2O 2
isoxime JMeOH 212-213 MeOH 2
isoxime hydrobromide 275-276 H2O 2
isoxime methyl ester? hydriodide 275-276 H2O 2
isoxime methyl ester? hydro-
bromide? . . . . . 252-254 H2O 2
O-desmethylflavothebaone hydro-
bromide 2JH 2 O . . . . 285d. H2O 2
Dibromoflavothebaone trimethyl
ether . . . . . 270-272 EtOH 2
Dihydroflavothebaone hydrochloride 350 H2O + 242-0 U MeOH 2
Dihydroflavothebaone trimethyl
ether 238 MeOH needles + 213-0 16 OHCl. 2
oxime . . . . . 256-257 EtOH 2
Mavothebaone trimethyl ether 160-161 40% plates -125-6 20 CHCl, 2, 4
methine EtOH
methiodide . . . . 295 H2O -104-7 20 H2O 2, 4
N-free product C21H21O5 . 182 MeOH yellow 4
plates
N-free product O21H22O, ? 247 MeOH prisms + 764 19-5 CHCI3 4
Base from acetolysis 249 MeOH plates + 176 18 CHCl3 4
N-free product from acetolysis 230-233 4
B I B L I O G R A P H Y TO C H A P T E R X X I
1. SANDEBMANN, Ber., 1938, 7 1 , 648. 5. KANEWSKAYA and MITBYAGINA, J.
2. SOHOPF, VON GOTTBEBG, a n d P E T E I , Gen. Ghem. U.S.S.R., 1947,17, 1203.
Ann., 1938, 536, 216. 6. B E N T L E Y , ROBINSON, and WAIN,
3. B E N T L E Y a n d THOMAS, unpublished J.G.S., 1952, 958.
work. 7. KANEWSKAYA, YASKINA, and MITBYA-
4. and DOMINGUEZ, unpublished GiNA, J. Applied Ghem. U.S.iS.R.,
work. 1945, 18, 374.
XXII
APOMORPHINE
WHEN morphine [i] is heated with concentrated hydrochloric acid at
140-145 C. a deep-seated rearrangement of the molecular structure
occurs and a new base, apomorphine [n], is produced [I]. Several other
methods of preparation of this base have been recorded as follows:
heating morphine with phosphoric acid [2] or zinc chloride [3-5];
heating chlorocodide [6] or codeine [7] with concentrated hydrochloric
acid; and by passing gaseous hydrogen chloride through a solution of
morphine in syrupy phosphoric acid [8-9]. The last-mentioned method
gives very good yields. The substance obtained by the action of mod-
erately concentrated sulphuric acid on morphine [10-13] is probably
apomorphine sulphonic acid [14]. Apomorphine-3-methyl ether (apo-
codeine) can be prepared by heating codeine with phosphoric acid [15],
oxalic acid [16-20], or zinc chloride [21-24], and apomorphine-3-ethyl
ether by the action of zinc chloride on morphine-3-ethyl ether [24].
PROPERTIES
Though its salts were soon obtained crystalline, the free base was
long thought to be amorphous and was not crystallized until 1904 [16].
Apomorphine readily undergoes aerial oxidation, and both the base and
its salts turn green on exposure to the air. The oxidation is particularly
rapid in alkaline solution when apomorphine, like pyrogallol, absorbs
oxygen [25]. The base can only be obtained crystalline by liberation
from its salts with sodium bicarbonate in the absence of air, followed
by extraction with ether or chloroform and crystallization from the
latter solvent in an atmosphere of nitrogen.
DETECTION
The following colour tests have been recorded for apomorphine.
Reagent Colour References
cone. H 2 S 0 4 + H - C H O violet > rose blue-black 26
cone. H 2 SO 4 -I-hexamethylenetetramine brown-violet 26
cone. H 2 S O 4 + a m m o n i u m vanadate blue 26
cone. H 2 S 0 4 + a m m o n i u m molybdate blue 26
oono. H 2 SO 4 +sodium arsenate dark blue 27
cone. H 2 S 0 4 + K R e 0 4 greyish-violet s- violet 28
oono. H a S 0 4 + a m m o n i u m persulphate green ?- blue 26
oono. H 2 S0 4 +selenio acid dark violet 26
oonc. H 2 SO 4 , 40O., 7 min.; dilute; add brown, slowly develops purple U
oono. NH 4 OH fluorescence
PbO,-|-HOAo warm, flltor; add cone. dark green 29
HgSO 4
CH. XXII APOMORPHINE 303
CHEMICAL PROPERTIES
Apomorphine was shown to have the composition C 17 H 17 O 2 N by
Matthiessen and Wright [I]. Mayer and Wright [25] obtained pyridine
by the destructive distillation of the alkaloid, but were unable to identify
any of the products of oxidation. The alkali-solubility of the base and
the formation of a dibenzoyl-derivative indicates t h a t apomorphine
contains two phenolic hydroxyl groups, and the colour with ferric
chloride and ease of oxidation suggest that these are present in a
catechol system.
The two phenolic groups differ markedly in reactivity. Methylation of
apomorphine affords apomorphine-3-methyl ether, identical with apo-
codeine, which on further methylation gives apomorpbine-3:4-dimethyl
ether [18]. A monoacetyl-derivative has also been prepared [63].
HOHANH DEGRADATION
The nitrogen atom of apomorphine [n] carries one methyl group [64],
and is apparently contained in a ring as it is not eliminated from the
molecule until the second step of exhaustive methylation. Alkaline
degradation of apomorphine-3:4-dimethyl ether methiodide affords two
products t h a t arise b y fission of the nitrogen ring in eaoh of the two
possible ways, namely the optically inactive apomorphine dimethyl
ethor mothino [ui] and tho optioally active wwmothino [iv], wliioh still
304 APOMORPHINE CH. XXII
OTHER DEGRADATIONS
When apomorphine is treated with excess of benzoyl chloride scission
of the nitrogen-containing ring occurs with introduction of a benzoyl
group on the nitrogen, the product being tribenzoylapomorphine [x]
[16], That this is an aromatic phenanthrene derivative is revealed by
its oxidation to a phenanthrene quinone [xi]; no groups are lost during
this roaotion, thus the 9:10 positions must be free of substituents [70].
OH. XXII AP0M0RPHINE 305
SYNTHESIS
Two syntheses of apomorphine dimethyl ether have been recorded,
as follows.
(a) Spath and Hromatka, making use of the Bischler-Napieralsky
tsoquinoline and Pschorr phenanthrene syntheses condensed 2-nitro-
3:4-dimethoxyphenylacetyl chloride [xin] with /?-phenylethylamine
[xiv] and converted the resulting amide [xv] to the benzyldihydroiso-
quinoline [xvi] by boiling it with phosphorus pentoxide in xylene.
McO
McO' CH2
NO2 CN ^ Y * > - C N M e O ^ f >-C00H r A
[XX] NaOEt ^0, I _ ^O 2 L ~^^
NMe NMe
OH
UO - [XXI]
[XXII] [XXIII] [XXIV]
6H
NMe
Gulland [81] has pointed out t h a t not only did Pschorr and Avenarius
fail to isolate the intermediates in their synthesis, but also this method
had previously been attempted [82], not only for apomorphine dimethyl
ether but for other aporphine bases as well, and t h a t in every experi-
ment in a large number carried out under a variety of conditions,
fission of the primary condensation product occurred with regeneration
of the starting materials or their derivatives. No aporphine base, not
even an aminobenzylisoquinoline, was ever obtained, and in the specific
case of the attempted synthesis of apomorphine dimethyl ether, in
place of the 'apomorphine dimethyl ether methiodide', m.p. 195 C ,
reported by Pschorr and Avenarius, only N-methyl-l:2:3:4-tetra-
hydrotsoquinoline, m.p. 192 C , was obtained. No successful repetition
of this synthesis has ever been published. A thorough criticism of the
claim and of the experimental work is given by Gulland and Virden [82].
D E R I V A T I V E S OP A P O M O R P H I N E
Apomorphine- 1-sulphonic acid is obtained by the sulphonation of
apomorphine with ice-cold concentrated sulphuric acid [14, 83-84].
I t is probably identical with the substance obtained b y the action of
moderately concentrated sulphuric acid on morphine [10-13].
' 2-nitrosoapomorphine', prepared by Wieland and Kappelmeier from
' 2-nitrosomorphine' [85], is presumably 2-nitroapomorphine [86-87].
2-aminoapomorphine [85], 2-phenylazoapomorphine [88-89], and 2-
(ji-chlorophenylazo)-apomorphine [89] can be prepared by the re-
arrangement of the corresponding substituted morphines.
The demethylation of morphothebaine (see Chap. X X I I I ) affords
6-hydroxyapomorphine, which is even more sensitive in alkaline solution
than apomorphine [90].
T H E M E C H A N I S M OP THE M O R P H I N E - > A P O M O R P H I N E
CONVERSION
I n warm concentrated hydrochloric acid morphine adds one molecule
of hydrogen chloride at the 4:5-oxygen bridge and suffers replacement
of the alcoholic hydroxyl group by chlorine, subsequently or simul-
taneously undergoing an a:y-shift of the substituent giving dichloro-
dihydrodesoxymorphine hydrochloride [xxvn]. The latter readily loses
hydrogen chloride even in hot water, giving /?-chloromorphide [xxvi],
from which it may be regenerated by the action of hydrogen chloride.
That /3-chloromorphide [xxvi] is an intermediate in the production of
[xxvn] from morphine is shown by the fact that if the reaction is stopped
when crystals of [xxvn] first appear, morphine and /?-chloromorphide
can be isolated from the solution in approximately equal amounts,
togethor with [xxvn]. Under the conditions of the morphine - > apo-
morphine conversion both /3-ohIoromorphide and [xxvn] give yields of
308 APOMORPHINE OH. XXII
+HCl
NMa
[XXIX]
-2 H Cl
On the basis of the above Small, Faris, and Mallonee [15] have
advanced the following mechanism for the morphine > apomorphine
conversion. Three stages are envisaged:
(a) Replacement of the alcoholic group of morphine [i] by chlorine
and subsequent or simultaneous a.: y-shift of the substituent giving
/3-chloromorphide [xxvi].
(6) The cyclic ether group of [xxvi], activated by the 6:7-double
bond, undergoes addition of hydrogen chloride to yield [XXVII].
(c) Rearrangement of [XXVII] to apomorphine [n] via [XXVIII] or
[xxix] with loss of two molecules of hydrogen chloride.
I t is believed t h a t apocodeine is formed in a similar way, and support
for the mechanism is cited in the fact t h a t i/r-codeine, in which the
a:y-shift of (a) has already occurred, gives a somewhat better yield
[15, 17].
However, though such a mechanism is possible in the specific case
of the conversion of morphine to apomorphine in hydrochloric acid, it
cannot bo operative in phosphoric acid or in the production of apo-
oodeino by boating codeine with oxalic acid. I t is possible to give a
CH. XXII APOMORPHINE 309
general mechanism applicable to all cases and also to the conversion of
thebaine to morphothebaine (Chap. XXIII) and thebenine (Chap.
XXV) and of 'thebaine-hydroquinone' to flavothebaone (Chap. XXI)
as follows.
-H2O -H 2 O
HO
H*
APOMORPHINE
4O
2
U)
O
Q
'3-5
3-O
2-5
20OO 25OO 3000 35OO
WAVELENGTH A
FIG. 15.
Solvent
for Crystal Specific
Compound m.p. "C. recrystn. form rotation Temp. Solvent Befs.
( subl. 98
Apomorphine . . . . I CHCl, 16
hydrochloride . Ha0 prisms -30-5* 16 H2O 16,99
sulphate . 100
silicotungstate . 101
mcthochloride . 205-210 BtOH 102-103
methobromide MeOH 180 MeOH 102-4
inethonitrate acetone plates 102-103
mothomethylsulphate 102-103
Monoacotylapomorphine ? 63
Dlacotylapomorphine 129 -67-3 dil.HCl 16
mothlocUdo 233 -47-2 ACjO 16
Trlacotylapomorphlno . 137 71
DllmiiBoylnpomorpliIiio . IGO-I58 EtOH prisms + 43-4* 17 CHCl8 16
liiolhloilldo . , 220-280 noodloB 16
Wi
APOMORPHINE 311
Solvent
for Crystal Specific
Compound m.p. "G. recrystn. form rotation Temp. Solvent Befs.
Dibenzoylacetylapomorphine . 156-158 16
Tribenzoylapomorphine 217-218 CHCl3 needles 16, 70
Tribenzoylapomorphine cruinone 178-179 yellow 70
needles
phenylhydrazone 235-236 70
Apomorphine-3-methyl ether ( + 66-8 22 BtOH 16
(Apocodeine) j 105-110 -90-0 15 EtOH 17-18
121-121-5 MeOH prisms -97-0 24 BtOH 15
hydriodide . . . . 288
methiodide . . . . /229-230 + 10-4 21 H1O 16
1230-233 -17-0 15 MeOH
Monobenzoylapomorphine-3-methyl
ether 85-90 BtOH needles 16
Diacetylapomorphine- 3-methyl ether
-H2O 130 16
MonoacetyIapomorphine-3-methyl
ether methiodide 241-242 -39-0 15 H2O 16
Apomorphine dimethyl ether . oil -148-0 15 BtOH 18
hydriodide . . . . C. 220 -49-0 15 EtOH 18
d-bitartrate . . . . 177-178 72
methiodide . . . . 195 -46-0 15 EtOH 18, 16
Benzoylapomorphine dimethyl ether 166-5 72
2-nitroapomorphine > 300 EtOH red 85
needles
hydrochloride . . . . D. > 200 85
2-aminoapomorphine amorph. 85
hydrochloride . . . . 260-265 85
2-phenylazoapomorphine > 310 88-89
2-(2>-chlorophcnylazo)-apomorphine . 89
6-hydroxyapomorphinehydrobromide 261-262 H2O needles 90
Apomoiphine-1-sulphonic acid. > 300 needles 84
14, 83
Apomorphine dimethyl ether methino 16
hydrochloride . . . . 220-221 needles 16
methiodide . . . . 242-244 H2O plates 16
Apomorphine dimethyl ether dihydro-
methine . . . . . 70-5-71-6 leaflets 69
methiodide . . . . 240 69
Apomorphine dimethyl ether iso-
methine . . . . . + 138-6 65
3:4-dimethoxy-8-vinylphonanthrone 80 EtOH plates 16
pierate . . . . . 128 H2O + violet 16
EtOH needles
dibromide . . . . 145-147 HOAc needles 16
tribromide . . . . 158-159 leaflets 16
pentabromide . . . . 153-154 petrol rods 66
3:4-dimethoxy-8-(a: /9-dihydroxy-
ethyl)-phenanthrene . 145 EtOH leaflets 66
diacetate . . . . . 126-127 MeOH prisms 66
3:4-dimethoxyphenanthrene-8-
carboxylic acid . . . . 196 HOAc needles 16
ethyl ester . . . . 81-83 EtOH rods 67
hydrazide , 194-195 BtOH needles 67
methane . . . . . 164-165 EtOH needles 67
3:4-dimethoxy-8-aminophenanthrene
hydrochloride . . . . 29Od. H2O needles 67
3:4-dimethoxy-8-hydroxyphenan-
threne . . . . . 182-183 BtOH prisms 67
3:4:8-trimethoxyphenanthrene 138 EtOH 67
pierate . . . . . 129 needles 67
dibromide . . . . 139-140 67
a-Ethylphenanthrene from zinc-dust
distn. of 3:4-dimethoxy-8-vinyI-
phenanthrene . . . . 109-110 MeOH leaflets 66
piorato . . . . . 138-140 66
qninono . . . . . 187-188 OO
0-Ethylphoiianthreno from same
source OO
312 APOMORPHINE CH. X X I I
DEGRADATION
Howard prepared what he believed was monoacetylmorphothebaine
[1], but this was subsequently proved to be a triacetyl-derivative [7],
and its formation involves scission of the nitrogen-containing ring [8],
though this was not at first recognized. Similarly the base on heating
with benzoyl chloride gives a tribenzoylmorphothebaine [iv] [9], which
is a fully aromatic phenanthrene derivative, and can be oxidized with
chromic acid to tribenzoylmorphothebainequinone. The latter is not
orystallino b u t gives a crystalline phenylhydrazone C 45 H 35 O 7 N 3 and,
with o-phenylenediamine, a crystalline azine C45H33O8N3, and may be
hydrolysod to N-benzoylmorphothebaine quinono, which gives a
OH. XXIII MORPHOTHEBAHsTE 315
EXHAUSTIVE METHYLATION
Morphothebaine affords with difficulty a dimethyl ether on methyla-
tion in isoamyl ether with nascent diazomethane [5]. When the phenolic
base is heated with sodium methoxide and methyl iodide, and when the
methiodide is heated with methyl sulphate and alkali, methylation and
Hofmann degradation occurs, the product being morphothebaine di-
methyl ether methine methiodide [v], further degradation of which
yields 3:4:6-trimethoxy-8-vinylphenanthrene [vi], trimethylamine,
and a grey, sandy powder, sintering between 200 C. and 300 C ,
having the composition (C19H18Og)n, which is probably a polymer of
[VI] [9].
has been synthesized from [ix] by reduction, ring closure, and decarb-
oxylation of the resulting [x]. When [x] is heated in glacial acetic acid
demethylation of the 8-methoxyl group occurs, the product being the
lactone [xi] [12]. This recalls the behaviour of the azide and nitrile of
3:4:8-trimethoxyphenanthrene-5-carboxylic acid, which can readily be
converted to the lactone [xn] (see Chap. XXV) [13].
MeO MeO
MeO MeO
COOH
MeOy^. MeOY^S
MeoA^J\ CH, MeoA^\
N NO2 NO2
2 00Cl PCL
[XIII]
MeO^/k^ MeO
[XIV] [XV]
METATHEBAINONE IN METHANOL
METATHEBAINONE IN
CONC. HCI.
40
2
CO
UX/.' A \ \ \
THEBAINE IN
QJ . CONCHCI.
3S
METATHEBAINONE IN \ \.
CONC. HCI / ^ \
THEBAINE IN METHANOL \
3O-
20OO 25OO 3000 35OO 40OO
WAVELENGTH A
Fio. 16.
MeO
NMe
MeO
NMe
MeO
H-
MeO
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Sefs.
3:4:6-trimethoxy-8-aminophenan-
threne hydrochloride . 250 H2O needles 11
3:4:6-trimethoxy-8-hydroxyphenan-
threne . . . . . 11
3:4:6:8-tetramethoxyphenanthrene 108-109 MeOH needles .. 11
picrate . . . . . 147-148 11
B I B L I O G R A P H Y TO C H A P T E R XXIII
1. H O W A R D , Ber., 1884, 17, 527. 14. GITIXAND and H A W O R T H , ibid. 2083.
2. SOHOPF a n d BORKOWSKY, Ann., 1927, 15. K O N D O a n d SANADA, J. Pharm. Soc
458, 148. Japan, 1931, 5 1 , 509.
3. HOWARD and R O S E R , Ber., 1886, 19, 16. W I E L A N D and K O R A L B K , Ann., 1923,
1596. 433, 267.
4. K N O R R , ibid., 1903, 36, 3074. 17. FRETOTD, Ber., 1905, 3 8 , 3234.
5. KiJBiH-, Aroh. Pharm., 1914, 252, 211. 18. FALTIS, Arch. Pharm., 1917, 2 5 5 , 85.
6. GOTO, Bull. Ohem. Soc. Japan, 1930, 19. F R E U N D a n d S P E Y E R , Ber., 1916, 4 9 ,
5, 311. 1287.
7. FRETTND and H O L T O F F , Ber., 1899,32, 20. GULLAND a n d R O B I N S O N , Mem. Proc.
168. Manchester Lit. Phil. Soc, 1925, 69,
8. Tim-EN-BATT, Bull. Soc. OHm., 1914, 79.
(4), 17, 67. 2 1 . PSCHOKR, P I A F F , and HERRSOHMANST,
9. K N O R R and PSOHOBR, Ber., 1905, 3 8 , Ber., 1905, 3 8 , 3160.
3153. 22. ROBINSON, Proc. Boy. Soc, 1947,
10. PSCHORB, a n d H A L L E , ibid., 1907, 4 0 , 135 B , v - x i x .
2004. 23. Nature, 1947, 160, 815.
11. and R E T T B E R G , Arm., 1910,373, 24. VON ATJWERS and ZIJSSLER, Ann.,
51. 1921,425,217.
12. and K N O F F L E H , ibid., 1911, 382, 25. CROSSLEY and L B SUEUR, J.C.S.,
50. 1902, 827.
13. GULLAND a n d V I R D E N , J.O.S., 1928, 26. GIRARDET, ibid., 1931, 2630.
921.
0417,1 Y
XXIV
ISOTHEBAINE
D TJ B, i N G the period of growth of the oriental poppy, Papaver orientate,
the plant contains appreciable amounts of thebaine, b u t during late
fall, after ripening and dying of the aerial plant, little, if any, of this
alkaloid is to be found, but at this time an optically active base,
isomeric with thebaine, may be isolated from the root of the poppy.
This base, called isothebaine, was first isolated by Gadamer [1-2] as an
unidentified phenolic alkaloid and subsequently examined by Klee [3].
I t has also been shown to be present in Papaver bracteatum [4].
DETECTION
Klee [3] recorded the following colour tests for the alkaloid:
Reagent Colour
cone. H 2 SO 4 . . . . . colourless
cone. H a S0 4 -|-conc. H N O 8 pale yellow-
cone. H 2 SO 4 +sodium molybdate blue > olive green
cone. H 2 S 0 4 + a m m o n i u m vanadate . bright olive green
cone. HNO 3 . . . . . dark violet
COMPOSITION
Isothebaine has the composition CI 9 H 2 XO 3 N, contains one phenolic
hydroxyl group, one N-Me group, and two -OMe groups [3]. Acetyla-
tion of the base in pyridine affords a monoacetyl-derivative [4], but
boiling the base in acetic anhydride results in scission of the nitrogen-
containing ring and production of a diacetyl-derivative, which is
optically inactive [3-4]. I n this reaction isothebaine resembles apo-
morphine and morphothebaine.
HOEMANN DEGRADATION
Methylation of isothebaine with nascent diazomethane affords the
methyl ether for which the structure [i] was suggested by Klee [3].
The Hofmann degradation of the methyl ether methiodide yields two
methine bases, isothebaine methyl ether methine [n ?], which is optically
inactive, and isothebaine methyl ether isomethine [in ?], which is
optically active [3, 5]. Kiselev and Konovalova [5] have also noted the
production during the reaction of trimethylamine and the same nitrogen-
free product as is obtained by the further degradation of either the
methine or the isomethine [3-6]. This nitrogen-free product is a tri-
methoxyvinylphenanthrone, possibly [iv] [3, 6], and can be oxidized by
OH. X X I V ISOTHEBAINE 323
y is \ V J * \ """
X
O
O ISOTHEBAINE \\
O \ \
_l _ i i \ \
l-OH i I \ \
3000 35OO 4000 45OO
FREQUENCY
FIG. 17.
NO 2 I
MeO-^
NH
MeO
MeO
MeO
Il
/CH
CH(OEt)2
[XI]
Failure to prepare the required benzyKsoquinoline derivative either
by Bischler-Napieralsky ring closure or through condensation of the
pseudo-base from 7-methoxytsoquinoline with 3:4-dimethoxy-2:6-
dinitrotoluene has more recently been reported by Schlittler and
Muller [6]. These workers, finding t h a t the condensation of substituted
desoxybenzoins with amino-acetals according to the method of Pom-
meranz and IYitsch also failed to give the required isoquinoline,
attempted the synthesis of isothebaine methyl ether in the following
way.
The condensation of 2-bromo-5-methoxyphenylacetic acid with
2-nitro-3:4-dimethoxybenzaldehyde followed by reduction and cycliza-
tion b y Pschorr's method affords 3:4:5-trimethoxy-8-bromophenan-
threne-9-carboxylic acid [VIII] in 10 per cent, overall yield. Debromina-
tion of this followed by sodium amalgam reduction resulted in the
9:10-dihydro-derivative [ix], which was converted by the Curtius
degradation to 3:4:5-trimethoxy-9-amino-9:10-dihydrophenanthrene
[x]. The latter, on condensation with glyoxal diethylacetal, afforded
[xi], which was cyclized by concentrated sulphuric acid yielding two
bases; one, m.p. 228 C , was non-phenolic and gave an ultra-violet
absorption spectrum t h a t differs profoundly from t h a t of isothebaine;
the other, m.p. 176 C , was phenolic, but the analytical data show t h a t
it oannot be a derivative of isothebaine [6].
OH. X X I V ISOTHEBAINE 325
B I B L I O G R A P H Y TO C H A P T E R X X I V
1. GADAMEB, Arch. Pharm., 1911, 2 4 9 , 7. VONGEEICHTEN and DITTMEB, Ber.
39, 1906, 39, 1718.
2. Z. angew. Chem., 1913, 26, i. 8. PSCHOBB and K O C H , Ann., 1912, 3 9 1 ,
625. 40.
3. K L E E , Arch. Pharm., 1914, 252, 211. 9. B B N T L E T a n d ROBINSON, Experientia,
4. KiSBIiBV and KONOVALOVA, J. Gen. 1950, 6, 353.
Chem. V.S.S.M., 1948, 18, 142. 10. J.O.S., 1952, 947.
5. ibid., 1949, 19, 148. 11. GIBABDET, ibid., 1931, 2630.
6. SCHLITTLEE a n d MTILLEB, HeIv. Ohim. 12. CAIZJOW, GOTLAND, and HAWOBTH,
Acta, 1948, 3 1 , 1119. J.O.S., 1929, 1444.
XXV
THEBENINE
PROFOUND modification of the structure, with migration of the basic
side-chain and reversion to a fully aromatic phenanthrene derivative,
occurs when thebaine [i] [1] or codeinone [n] [2] is heated with dilute
hydrochloric acid, the product being the phenolic secondary amine
thebenine [in]. Triacetylthebenine is produced when ^r-codeinone [iv]
is heated with acetic anhydride [3], and thebenine-8-methyl ether
(methebenine), 8-ethyl ether (ethebenine), and 8-propyl ether (prothe-
benine) can be prepared by heating thebaine or codeinone with hydro-
chloric acid and methyl, ethyl, and propyl alcohol respectively [2, 4].
Methebenine, which can be hydrolysed to thebenine by hot 20 per cent,
hydrochloric acid [4], is also obtained by the action of stannous chloride
and acetic anhydride on thebaine [5].
with the compound synthesized by Pschorr and Busch [14]. I n the same
way ethebenine can be degraded through 3:4-dimethoxy-8-ethoxy-5-
vinylphenanthrene and 3:4-dimethoxy-8-ethoxyphenanthrene-5-car-
boxylic acid to 3:4-dimethoxy-8-ethoxyphenanthrene [9-10], the latter
being identical with an authentic specimen prepared by synthesis [10].
3:4:8-Trimethoxyphenanthrene-5-carboxylic acid [vm] can be con-
verted through the ester to the azide [ix], but attempts to degrade the
latter to the 5-amino compound failed; nitrogen was lost and the
product was identified as the lactone [x] of 4-hydroxy-3:8-dimethoxy-
phenanthrene-5-carboxylic acid [ H ] .
REDUCTION
Thebenine cannot be reduced electrolytically or with sodium and
alcohol, but catalytic hydrogenation [15] or reduction with sodium
hydrosulphite [16] converts it to 9:10-dihydrothebenine [xni], which is
too unstable to survive degradation. The dimethyl ether, however,
can be degraded to 9:10-dihydromethebenol, the 4-methoxyl group
being demethylated during the degradation [16]. (9:10-Dihydromethe-
benol was originally given the inaccurate name 'methoxydihydrothe-
benol' [16].) An oil, possibly dihydropyrene, results from the reduction
of 9:10-dihydromethebenol with hydriodic acid and red phosphorus
under pressure [16].
Being a secondary amine, thebenine reacts with phenyHsothiocyanate
to give thebenylphenylthiourea [xiv] [7].
During investigations of the reaction between cyanogen bromide and
cyclic bases von Braun [17] discovered that thebaine reacts with this
oompound to give a substance subsequently identified as cyanonorthe-
benine [xv] [18]. This cannot be prepared from thebenine, nor can it be
hydrolysod to northebenine. On oatalytio reduction it absorbs eight
OH. X X V THEBENINE 329
T H E M E C H A N I S M OF THE T H B B A I N E - THEBENINE
TRANSFORMATION
Several mechanisms have been proposed for the conversion of the-
baine to thebenine. Those of Ereund and Speyer [22] and of Gulland
and Robinson [23] are based on bridge formulae for thebaine t h a t are
now abandoned. However, Gulland and Robinson [23] suggested t h a t
the aldehyde [xx] is a precursor of thebenine [in] to which it may be
converted by dehydration, a view still believed to be substantially
correct. The mechanism suggested by Faltis [24] is based on an im-
possible formula for thebaine and need not be considered.
Schopf and Borkowsky [25] postulated the 1:4-addition of water to
the dienoid system of thebaine [i] to give [xxi], which could then
undergo hydrolysis and i/r-codeine transformation to [xxn]. The ether
bridge was then behoved to break with introduction of a C-5:14 double
bond, necessitating migration of the side-chain from 0-14 to 0-5,
330 THEBENINE OH. X X V
resulting in fission of the C-9:N link for steric reasons, followed by-
aromatizing dehydration. Gulland and Virden [11], however, pointed
out that [xxi] in its hydrolysed form is 14-hydroxycodeine, which is
unaffected by hot dilute hydrochloric acid, and does not give triacetyl-
thebenine on heating with acetic anhydride. (This may not be a valid
objection as it is very doubtful whether 14-hydroxycodeine has in fact
a structure analogous to [xxi]see Chap. XVIII.)
Solvent
for Crystal
Compound m.p. C. recrystn. form Eefs.
Thebenine . . . . . . amorph. 1, 7
hydrochloride-3H 2 O . . . . 235 H2O yellow 1, 7
cryst.
sulphate . H a 0 209-210 H2O yellow 1, 7
leaflets
- thiocyanate . . . . . . cryst. 1
platinichloride . . . . . amorph. I
mercurichloride . . . . . prisms 1
oxalate H 2 O . . . . . . 276-276 H2O needles 1
N-methylthebenine methiodide 206-208 H2O 7
Triacetylthebenine . . . . . 160-161 EtOH 4, 3, 2
Methebenine . . . . . . 165-167 EtOH 4, 2
hydrochloride . . . . . 250 4
hydriodide . . . . . . 195-198 4
sulphate . . . . . . 238-5 4
N-methylmethebenine methiodide 215 H2O + 4
EtOH
N-methylbenzoylmethebenine methiodide 271 8
Diacetylmethebenine . . . . 176 4
Dibenzoylmethebenine . . . . 159 8
N-methylthebenine dimethyl ether
methiodide . . . . . . 247 8
methomethylsulphate . . . . 283-285 11
Ethebenine . . . . . . amorph. 4
hydrochloride . . . . . 248 H2O + 4
EtOH
hydriodide H 2 O . . . . . 206-207 4
N-methylethebenine methiodide 215 4
N-methylethebenine-4-methyl ether
methomethylsulphate . . . . 241 9
methiodide . . . . . . 262 9
Diacetylethebenine . . . . . 168 4
Prothebenine . . . . . . 172-173 EtOH 4
- hydrochloride . . . . . 220-221 4
hydriodide . . . . . . 212-213 4
N-methylprothebenine methiodide 202 4
9:10-dihydro thebenine . . . . D.147-148 rods 16
hydrochloride . . . . . 237-238 leaflets 16
thiosulphate . . . . . 194-195 16
N-methyl-9:10-dihydrothebenine hydriodide 130-131 H2O leaflets 16
N-methyl-9:10-dihydrothebenine dimethyl
ether . . . . . . .
methiodide . . . . . . D . 245 16
methomethylsulphate . . . . D.270-271 16
Thebenylphenylthiourea . . . . 85 7
Thebenol 186-188 acetone 6-7
sodium salt . . . . . . 210-212 6
Acetylthebenol . . . . . . 102-103 7
Methebenol . . . . . . 133-134 HOAc plates 4, 7-8
picrate . . . . . . . 106 8
Monobromomethebenol . . . . 148-149 8
E thebenol . . . . . . 103-104 HOAo 4
Prothebenol . . . . . . 103-105 HOAc 4
Dihydromethebenol . . . . . 133-134 16
Northebenol . . . . . . 202-203 7
'iodhydrin' . . . . . . D . 270 7
3:4:8-trimethoxy-5-vinylphenanthrene . 122-6 EtOH plates 8
piorate . . . . . . . 110 8
3:4-dimothoxy-8-othoxy-fl-vinylphenanthrono 78 potrol plates 9
3 : 4 : B-trlmotlioxyphonanthrono-C-carboxylio I 219-221 0
aoid ( 830-237 HOAo noodloi 11
332 THEBENINE OH. X X V
Solvent
for Crystal
Compound m.p. G. recrystn. form Refa.
3 : 4 : 8-tnmethoxyphenanthrene-5-carboxylic
acid m e t h y l ester . . . . . 149-151 MeOH 11
hydrazide . . . . . . 177 BtOH needles 11
azide . . . . . . . D . 65 11
3:4-dimethoxy-8-ethoxyphenanthrene-5-
carboxylic acid . . . . . 191 HOAc needles 9
3:4:8-trimethoxyphenanthrene 137-138 9
picrate . . . . . . . 129 9
3:4-dimethoxy-8-ethoxyphenanthrene 100 9
picrate . . . . . . . 119 9
3:4:8-trimethoxy-5-ethylphenanthrene . 112-113 EtOH needles 11
3 : 4 : 8 - t r i m e t h o x y - 5-aIdehydophenanthrene 151 benzene plates 11
('oxymothebenol') +petrol
oxime ^C 0 H 6 . . . . . 140-153 benzene leaflets 11
semicarbazone . . . . . 243-246 #ro 2 needles 11
3:4:8-trimethoxy-5-cyanophenanthrene 145-146 MeOH needles 11
Lactone of 3:8-dimethoxy-4-hydroxyphenan-
threne-5-carboxylio acid . . . . 246-247 HOAo needles 11
' Oxye the be nol' . . . . . 129 9
Cyanonorthebonine . . . . . 146-147 EtOH leaflets 18
Methiodide of p r o d u c t of reduction of cyanonor-
thebenine . . . . . . . 298-299 EtOH leaflets 18
Thebenidine . . . . . . 144-148 benzene 19
methiodide . . . . . . 240 19
3:8-dimethoxythebenidine ? [ x v m ] or [ x i x ] 229-230 orange 11
leaflets
picrate . . . . . . . D . 255 MoOH 11
Thebaicine . . . . . . amorph. 1
TriacetyKsothebenine . . . . . 167 15
I 191 15
1-bromotriacetyKsothebenine J 168-170 96% 27
EtOH
Triacetyl-9:10-dihydroMothebenine 182-183 15, 27
B I B L I O G R A P H Y TO C H A P T E R X X V
1. H E S S B , Ann., 1870, 153, 47. 15. GOTO, SHISHIBO, a n d TAKTJBO, Ann.,
2. K N O B B , Ber., 1903, 36, 3074. 1932, 497, 289.
3. a n d H O B L E I N , ibid., 1907, 40, 16. S P E Y E B a n d R O S E N F E L D , Ber., 1925,
2032. 58, 1120.
4. FBETJND a n d H O L T O F F , ibid., 1899, 17. VON BBATJN, ibid., 1914, 4 7 , 2312.
32, 168. 18. S P E Y E B and R O S E N P E L D , ibid., 1925,
5. SCHOPF and H I B S C H , Ann., 1931, 489, 58, 1125.
224. 19. VONGEBICHTEN, ibid., 1901, 34, 767.
6. FBETJND, Ber., 1894, 27, 2961. 20. CooKandTHOMPSON,J.O.8., 1945,395.
7. MICHAELS, a n d GOBEL, ibid., 21. BAMBEBGEE a n d GOLDSCHMID'T, Ber.,
1897, 30, 1357. 1894, 27, 1954.
8. P S C H O E B a n d MASSAOIU, ibid., 1904, 22. FBETJND a n d S P E Y B B , ibid., 1916, 4 9 ,
37, 2780. 1287.
9. a n d L O E W E N , Ann., 1910, 373, 23. GTJXtAND and ROBINSON, J.G.8.,
56. 1923, 980.
10. and Z E I D L E E , ibid. 75. 24. FALTIS, Arch. Pharm., 1917, 255, 85.
11. G T O L A S D a n d V I B D E N , J.O.S., 1928, 25. SOHOPP a n d BOBKOWSKY, Ann., 1927,
921. 458, 148.
12. SMAEL, J. Org. Ohem., 1942, 7 , 158. 26. K I S E L E V a n d KONOVALOVA, J. Gen.
13. FmnTran, Ber., 1910, 43, 2128. Ohem. U.S.S.R., 1948s 18, 855.
14. FsoiiOLut and BTJSOH, ibid., 1907, 40, 27. SOHOPT, PPHifTER, and HIBSOII, Ann.,
2001. 1932, 492, 213.
XXVI
SINOMENINE
T H E alkaloid sinomenin was first isolated from the stem and roots of
the Japanese plant Sinomenium diversifolius by Ishiwari in 1920 [I].
I t also occurs in Sinomenium acutum and probably in han-fangchi
[2-4]. Goto [5] first called the alkaloid cucoline, but subsequently
adopted the name sinomenine.
STBTJCTXJBB
Sinomenine was initially believed to have the composition C16H19O3N
[1], but was subsequently shown to be C19H23O4ISr [5-7]. The base is
soluble in alkali, gives a colour with ferric chloride, and affords alkali-
insoluble monobenzoyl- and monomethyl-derivatives [6], and is thus
recognized as a phenol. I n addition the molecule contains a tertiary
nitrogen atom, two methoxyl groups [5], one double bond [5, 7], and one
carbonyl group [5, 7]. The presence of a carbonyl group in dihydrosino-
menine has also been demonstrated [5, 7].
Phenanthrene and trimethylamine are obtained, together with an
unidentified quinoline-like oil when the base is distilled with zinc-dust
[5, 7], and the ease with which the alkaloid can be converted to non-
basic phenanthrene derivatives led Ochiai [7] to suspect the presence
of an easily ruptured tetrahydroisoquinoline system in the sinomenine
molecule. This was confirmed by the method of Gadamer (treatment
with ethyl chloroformate, when derivatives of tetrahydroisoquinoline,
but not of tetrahydroquinoline or tetrahydropyridine or piperidine,
suffer ring fission [8]) when sinomenine [i] was converted into a com-
pound C 25 H 32 O 8 NCl, in which the nitrogen-containing ring has been
ruptured, COOBt becoming attached to the nitrogen and Cl to a
carbon atom [7].
Sinomenine, like thebaine, is readily degraded to derivatives of phen-
anthrene on heating with acid anhydrides. The reaction with benzoic
anhydride affords dibenzoylsinomenol [n, R = </>-CO] [7, 9]. The
parent sinomenol [n, R = H] may be prepared by heating sinomenine
with 66 per cent, potassium hydroxide, ethylmethylamine also being
produced [9]; it can be methylated to dimethylsinomenol [n, R = Me],
which is also accessible, indirectly, from sinomenine methyl ether
(methylsinomenine) [1O]. Initially two series of sinomenol derivatives
w^ere thought to exist [9], but the higher-melting of these were sub-
sequently shown by moleoular weight determination to be dimolecular,
and to be dorived from 1:1 '-disinomonol [ H ] . The simple sinomenol
334 SIBTOMENINE OH. XXVI
MeO
HO
COOH
OMe
[VIII]
BBOMINATION
The bromination of sinomenine gives 1-bromosinomenine [5, 9, 21]
[xn], the structure of which is revealed by the reduction of the com-
pound to 1-bromodihydrosinomenine, dihydrosinomenine, and sino-
menine, and b y the fact that the diazo-reaction with 1-bromosino-
menine is much less intense than with sinomenine [21]. A second
substance is also produced by the bromination of sinomenine, but this
is non-phenolic and is discussed later under 1-bromosinomeneine.
OMe OMe
[IX] [X] [XI] [XII]
REDUCTION
The reduction of sinomenine yields a variety of products according
to the conditions.
(a) Catalytic hydrogenation yields dihydrosinomenine [xm] [5, 7, 9,
22]. Dihydrosinomenine, like sinomenine, reduces potassium per-
manganate in the cold [5].
(6) Zino-dust or amalgamated zinc and cold hydroohlorio acid also
reduoes sinomenine to dihydrosinomenine [23],
(c) Tho Clommonsen reduotion of sinomenine with amalgamated sdno
336 SINOMENINE OH. XXVI
OMe
[XVIII] [XIX]
OMe
[XX] [XXI] [XXII] [XXIII]
This conclusion was also reached by Goto and Mitsui [30], who
converted desmethoxydihydrosinomenine, established as the optical
antipode of dihydrothebainone [xv], to a ketodichloride [xxin] by
treatment with phosphorus pentachloride, and this on catalytic
reduction afforded desmethoxydesoxydihydrosinomonine [XJV]. In this
OH. X X V I SINOMENINE 339
sequence of reactions the hydroxy! group at C-4 must be retained
and the carbonyl group converted to methylene, and the product must
be the optical antipode of tetrahydrodesoxycodeine.
Goto and Mitsui then made an examination of the electrolytic reduc-
tion of numerous sinomenine derivatives, but in no case was the removal
of the hydroxyl group at C-4 observed. The compounds reduced in this
way were sinomenine, dihydrosinomenine, desmethoxydihydrosino-
menine, desmethoxydihydrosinomeninol, sinomeninol, dihydrosino-
meninol, sinomenine hydrate, and a- and /3-desmethoxysinomenine
hydrate [3O].
Further attempts to prepare Speyer and Siebert's ' dihydrothebaco-
dine' have all resulted in tetrahydrodesoxycodeine [32] (see Chap. XV).
Kondo and Ochiai [24, 31] suggested the name dihydrothebainan for
[xrv], but this has not been generally adopted.
T h e r e d u c t i o n of 1 - b r o m o s i n o m e n i n e proceeds parallel to the
reduction of sinomenine and gives:
(a) 1-bromodihydrosinomenine, dihydrosinomenine, and sinomenine
on catalytic hydrogenation [21];
(6) 1-bromodihydrosinomenine on reduction with zinc and cold
hydrochloric acid [33];
(c) 1-bromodesmethoxydesoxydihydrosinomenine, the optical anti-
pode of 1-bromotetrahydrodesoxycodeine, identical with the
product of bromination of desmethoxydesoxydihydrosinomenine,
on Clemmensen reduction [33-34];
(d) 1: l'-dibromo-bis-8:8'-desmethoxydihydrosinomenine, by sodium
amalgam reduction in alkaline solution. This compound may also
be prepared by the bromination of bis-8:8'-desmethoxydihydro-
sinomenine [33-34].
(e) The reduction of 1-bromodihydrosinomenine with sodium amal-
gam affords a 35 per cent, yield of 1-bromodesmethoxydihydro-
sinomenine, the optical antipode of 1-bromodihydrothebainone,
also obtained by the bromination of desmethoxydihydrosino-
menine [33-35].
[XXXII] [XXXIII]
1-BROMOSINOMENEINE
As already stated, the bromination of sinomenine gives two sub-
stances, 1-bromosinomenine and a compound first called 1-bromotso-
sinomenine [5, 9, 21], which was found to be non-phenolic [9] and to
have undergone some change in ring C [21]. This was subsequently
shown to be an oxidized substance, and was renamed 1-bromosino-
meneine [53]. I t is always obtained in 2-20 per cent, yield in the
bromination of sinomenine with one equivalent of bromine, the highest
yield being obtained by a rapid addition of the bromine, when a per-
bromide is precipitated; the oxidation to 1-bromosinomeneine occurs
during the decomposition of the perbromide. The yield of 1-bromosino-
meneine is increased to 40 per cent, by the use of two equivalents of
bromine [53].
The nature of this substance was first elucidated by Schopf and
Pfeiffer [54], who, following the conversion of dihydrothebainone [xLvni],
through 1:5-dibromodihydrothebainone [XLIX] to 1-bromodihydroco-
deinone [L] by bromination and treatment with alkali, and the similar
conversion of 14-hydroxydihydrothebainone [LI] to l-bromo-14-hydroxy-
dihydrocodeinone [LII], showed that 1-bromosinomeneine results in
80 per cent, yield from treating sinomenine with bromine and then
with alkali [54]. The intermediate 1:5-dibromosinomenine [LIII] has
boon isolated and converted to 1-bromosinomeneine by warming
CH. X X V I 1-BROMOSINOMENEINB 345
HOIMAHN DEGRADATION
The Hofmann degradation of 1-bromosinomeneine methiodide yields
1-bromosinomeneine methine [35] which has not been related to the
sinomenine methines and is here arbitrarily assigned the structure [LXI].
This degradation is in marked contrast to the degradation of codeinone
and thebaine methiodides, which leads- directly to fully aromatic
phenanthrene derivatives. 1-Bromosinomeneine methiodide on boiling
with methyl sulphate and alkali suffers complete degradation to 1-bromo-
3-methyl-6:7-dimethoxymorphenol [LXII] [35].
An entirely different methine base is obtained when 1-bromosino-
meneine methiodide is mixed with an equimolecular quantity of 10 per
cent, alkali at 20 0. and the mixture extracted with chloroform. This
base is 1-bromodehydrometasinomenine methine and it is allotted the
structure [LXIH] for the following reasons [60].
(a) It is soluble in alkali and gives a green colour with ferric chloride.
(6) One new methyl group, only, appears on methylation.
(c) It dissolves in concentrated sulphuric acid to give a deep blue
solution, and it gives I-bromodiacetylsinomenol quantitatively
on acetolysis and is therefore a methine base.
(d) The side-chain must be attached to C-13 or C-14, otherwise it
would not be eliminated during acetolysis.
(c) The base is yellow and gives a deep-red sodium salt.
OH. XXVI l-BROMOSINOMEJfEINE 347
OMe
[LXIII] [LXIV] [LXV] [LXVI]
S I N O M E N I N O N E AND I T S D E R I V A T I V E S
Sinomenine is an a:/3-unsaturated-a-methoxyketone and thus con-
tains a hydrolysable enol ether system and can be hydrolysed to an
a-diketone. Indeed sinomenine itself possesses some of the properties of
an a-diketone; e.g. it can reduce cold potassium permanganate solution,
Fehling's solution, and ammoniacal silver nitrate [6].
Hydrolysis of the enol ether may be achieved by 2N hydrochloric
acid at 100 C, and if the solution is neutralized with sodium carbonate
sinomenine hydrate [LXVII] is precipitated. This apparently exists in
the hemiacetal form, but the 7-methoxyl group is readily lost and for all
practical purposes sinomenine hydrate behaves as the a-diketone sino-
meninone [LXVIII, R = H], and gives a dioxime and disemicarbazone
[61].
0
HO'' "OMe
LLXVII] [LXVIII]
348 SINOMENINE CH. X X V I
When the base is liberated from the solution after hydrolysis with
ammonia instead of sodium carbonate a dimolecular base bis-des-
methylsinomenylidine is obtained instead of sinomenine hydrate [23],
and this base is also obtained by the action of ammonia on the latter [61].
I t is believed to arise from the self-condensation of the diketone, the
carbonyl group at C-6 in each molecule condensing with the active
methylene group at C-8 in the other, and the product is in fact a
quinone. The structure of the product is shown in essence in [LXIX].
The condensation of sinomeninone to bis-desmethylsinomenylidene is
analogous to the self-condensation of diacetyl to ^-xylene quinone [62].
1-Bromosinomenine may be hydrolysed to 1-bromosinomeninone
[LXVIII, R = Br], which exists in the a-diketone form [63]. The hydro-
gen bromide produced during the bromination of sinomenine will cause
hydrolysis of the product to 1-bromosinomeninone if the reaction
mixture is allowed to stand for several weeks [53]. 1-Bromosinomenin-
one, in marked contrast to sinomenine hydrate, gives a monomolecular
imide [LXX] on treatment with concentrated ammonia; the imide is
readily hydrolysed to the original diketone. The oxime hydrochloride
of [LXX] is believed to give 1-bromosinomeninone dioxime when precipi-
tated with sodium carbonate in the presence of hydroxylamine [63].
The optical antipode of 1-bromosinomeninone, viz. ()-1-bromosino-
meninone, is produced in small amounts during the conversion of
dihydrothebainone to 1-bromodihydrocodeinone [L] by bromination
and subsequent treatment with alkali. That it arises from the 7-bromo-
derivative is confirmed by its production when dihydrothebainone is
brominated with three equivalents of bromine and the resulting 1:5:7-
tribromodihydrothebainone [LXXI] treated with alkali, and when 1-
bromodihydrocodeinone [L] is treated with one equivalent of bromine
in the presence of potassium carbonate and methanol [64]. The forma-
tion of ()-1-bromosinomeninone [LXVIII, R = Br] from 1:5:7-tribro-
modihydrothebainone [LXXI] is analogous to the production of
buchucamphor [LXXII] from dibromomenthone [LXXIII] and from
dibromocarvomenthone [LXXIV] on treatment with alkali [65].
Br
[LXXI] [LXXII] [LXXIII] [LXXIV]
OMe O
[LXXVII] [LXXVIII]
BROMINATION
The bromination of sinomenine hydrate with three equivalents of
bromine and of 1-bromosinomeninone with two equivalents of bromine
yields 1:5:8-tribromosinomeninone, which is converted into 1-bromo-
sinomeninone by catalytic reduction, and to 1-bromodesmethoxydesoxy-
dihydrosinomenine on reduction by Clemmensen's method [69].
REDUCTION
Catalytic or sodium amalgam reduction of sinomenine hydrate results
in the loss of the 7-methoxyl group and production of two diastereo-
isomeric substances, a- and /3-dihydrosinomeninone [LXXIX] [70],
initially called a- and /J-desmethoxysinomenine hydrate [61]. These
compounds also result from the partial demethylation of dihydrosino-
menine [ x m ] , and so must have the structure [LXXIX] and be diastereo-
isomerie about 0-7, and not the alternative 6-hydroxy-7-keto form.
The a-isomer oan be converted into the /3 by 25 per cent, hydrobromio
aoid, 5 per oent. alkali, or by hoating over 200 C.; on warming with
thionyl ohlorido it undergoes dehydration to dosmethoxysinomonine,
350 SINOMENINE OH. X X V I
OH OH OH
[LXXIX] [LXXX] [LXXXI]
ACETOLYSIS
4:6-Diacetoxy-3-methoxyphenanthrene and triacetyk'sothebenine are
obtained by the acetolysis of sinomenine hydrate and the 1-bromo-
derivatives of these can be prepared in the same way from 1-bromosino-
meninone. Catalytic reduction of both triacetyHsothebenine and its
1-bromo-derivative affords triacetyl-9:10-dihydroisothebenine [55],
believed b y Schopf, Pfeiffer, and Hirsch [64] to be triacetyKsothebenine
when the same sequence of reactions was carried out on ()-l-bromo-
sinomeninone. /sothebenine is probably 4:6-dihydroxy-3-methoxy-5-
(/3-methylaminoethyl)-phenanthrene [LXXXII], or the 4:7-dihydroxy-
isomer [64]. On heating with sodium hydroxide and methyl alcohol at
80 C , 1-bromotriacetyMsothebenine yields a compound C 20 H 20 O 4 NBr in
7 per cent, yield; this is probably 1-bromo-N-acetyKsothebenine [55]
(see also Chap. XXV).
The acetolysis of 1-bromosinomeneine ketone [LXXVI] and of 1-
bromosinomenine methiodide gives l-bromo-3:4:6-triacetoxyphenan-
threne [59] (cf. the production of 3:4:6-triacetoxyphenanthrene in the
aootolysis of thebainone-A [xvm] [71]). Catalytic reduction of this
affords 3:4:6-triaootoxyphenanthrone [59].
OH. X X V I S I N 0 M E N I N 0 N E AND ITS D E B I V A T I V E S 351
HOFMANN DEGRADATION
The exhaustive methylation of the free diketones has not been
studied, b u t sinomenine hydrate on heating with ethyl sulphate and
alkali gives 5:5'-diphenanthrene derivatives as does sinomenine under
the same conditions [41].
Sinomeninone dioxime on boiling with potassium hydroxide is de-
hydrated to sinomeninone furazan [LXXXVI], and sinomeninone dioxime
methiodide is degraded by hot alkali to sinomeninone furazan methine
[LXXXVII] which on further degradation gives trimethylamine and
9:10-dehydro-()-thebenone ketone furazan [LXXXVIII]. The latter is
too sparingly soluble to permit reduction, but ()-thebenone ketone
furazan [LXXXIX] is obtained by the degradation of sinomeninone fura-
zan dihydromethine [48].
I n an exactly analogous manner 1-bromosinomeninone dioxime on
heating affords 1-bromosinomeninone furazan (also obtained by the
bromination of [LXXXVI]) which can be degraded to 1-bromosinomenin-
one furazan methine. The latter results in poor yield from the bromina-
tion of sinomeninone furazan methine [LXXXVII], but the chief product
of this reaction is, using two equivalents of bromine, 1:9 ?-dibromosino-
moninono furazan mothino, or, using throe equivalents of bromine,
1:9:lO-tribromosinomeninone furazan dihydromethino, whioh suflbrs
352 SINOMENINE CH. XXVI
MeO
MeO-
HO-
NMe
HOOC HOOC
HOOC- HOOC HOOC
[LXVIII] [XC] [XOIl [XOII]
OH. xxvi SINOMENINIC ACID AND ITS D E R I V A T I V E S 353
Methylsinomeninic acid [xci, R = H] and 1-bromomethylsinome-
ninic acid [xci, R = Br] are formed when methylsinomeninone [73]
and 1-bromomethylsinomeninone [44] respectively are oxidized with
hydrogen peroxide. Similarly the oxidation of 1-bromosinomeneine
ketone [LXXVI] affords 1-bromosinomeneinic acid [xcn] [73]. The ultra-
violet absorption spectra of [xo, R = H], [xc, R = Br], and [xci,
R = H] are very similar to that of sinomenine hydrate, which in turn
is almost identical with that of sinomenine [73].
Methylsinomeninic acid [xci, R = H] gives the acid chloride on
treatment with thionyl chloride and this is converted into the imide by
ammonia. On heating with acetic anhydride [xci, R = H] gives not
the anhydride but methyldihydrosinomenilone (see below) [75].
O
[XCHI] [XCIV] [XCV] [XCVI]
4-5
THEBAINONE-A (XVIII)
40
O
O
2
(O SINOMENINE (I)
Q
3-O
'PROTOSINOMENINE'
It was pointed out by Robinson [86] that thebaine [cix] could be
regarded as being derived from a laudanosine-type base by dehydration
and coupling of the two aromatic nuclei in a way analogous to the
polymerization of unsaturated substances, but that the orientation of
the substituents in the hypothetical precursor [ox] is unusual. However,
tho positions of the substituents in sinomenine [i] is suoh that it could
CH. X X V I 'PBOTOSINOMENINE' 357
theoretically arise in the plant by way of the normal type of laudano-
sine-base, 'protosinomenine' [cxi], by coupling in the positions marked
in [cxi] by an asterisk. This 'protosinomenine' has been synthesized in
two ways.
(a) Benzyfe'sovanillin was converted through the azlactone and
a-ketoacid to 3-benzyloxy-4-methoxyphenylacetic acid, the acid
chloride of which on condensation with j8-(3-benzyloxy-4-methoxy-
phenyl)-ethylamine gave the amide [cxn]. Bischler-Napieralsky
cyclization of [cxn] under the influence of phosphorus pentachloride in
chloroform afforded [CXIII], the methochloride of which on reduction
and debenzylation yielded 'protosinomenine' [oxi] [87].
HASUBANONINE
Recently a now alkaloid obtained from Stephania japonica Mors
fhaaunohakazura') has boon investigated and shown to bo very
358 SINOMENINE CH. XXVI
MeO NMe2
MeO
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Sefs.
Sinomenine . . . . . 161 and needles -707 26 EtOH 1, 6
182
hydrochloride 2H2O . D. 231 -82-4 17 H2O 5-6
hydrobromide . 231 5
hydriodide 233 5
nitrate 215 5
aurichloride amorph. 6
piorate C 140 1
methiodide 251 prisms 17,38
methomethylsulphate. 265 H2O 40
oxime 254d. . .1 5,7
semicarbazone . 264d. 7
Methylsinomenine 179 needles -29-6 14 CHOl3 66
methiodide 141 H2O 66
methomethylsulphate 245 MeOH prisms 40
oxime 139 prisms 66
Benzoylsinomenine 224 Et 2 O + prisms -85-0 4 CHCl3 66
henzene
methiodide 237d. H2O prisms 66
oxime 249d. MeOH prisms 66
1-bromosinomenine 153 f -2-6 25 5
I -8-9 6 CHCl, 53
hydrochloride 31-TjO . 116 H,0 58
hydrochloride (iuihyd.) 231 5
lvydrobrmnldo . 232 MoOH 53
iiiothlodklo 8(1 M
oxlmu . . null mm 6
1OH JJ. UU
360 SINOMENINE CH. X X V I
Solvent
for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp Solvent Refs.
1:5-dibromosinomenine . 197d. amorph. 55
hydrobromide . . . . 22Od. 55
l-bromomethylsinomenine noteryst. 44
methiodide . . . . 257 42,44
1-bromoethylsinomenine
ethlodide . . . . . 234 43
Sinomenine acftromethine 179 none prisms + 72-6 16 CHCl, 38
hydriodide . . . . 115-118 prisms 38
methiodide . . . . 212 -33-0 17 H2O 38
oxime . . . . . 204-205 MeOH prisms 38
Sinomenine roseomethine 163 + 135-7 16 CHCl, 38
methiodide . . . . 277 MeOH -48-3 17 H2O 38
Sinomenine jwfeomethine 172-173 CHCl,+ prisms + 437-8 17 CHCl, 38
Et 2 O
methiodide . . . . 209 H2O + 373-4 17 H2O 38
Methylsinomenme roseomethine
methomethylsulphate . 178 plates 40
Methylsinomenine tiiofeomethine'l 204d. EtOH prisms f+478-0 13 H2O \ 40
methomethylsulphate / 1 + 581-6 20 CHCl, S
1-bromosinomenine methine . 185d. MeOH yellow + 15-9 24 CHCl, 35
prisms
5-(hydroxymethyl)sinomenine . 260 MeOH prisms -40-7 29 CHCl, 37
methiodide . . . . 233 MeOH needles 37
oxime . . . . 240-245 amorph. 37
1:5-di-(hydroxymethyl)-sinomenine . 242 EtOH -74-4 30 MeOH 37
methiodide . . . . 210 MeOH 37
oxime . . . . . 200-215 amorph. 37
1-benzeneazosinomenine . 253d. ^NO 2 red plates 36
Cyanonormethylsinomenine 257 -14-4 14 24
Cyanonorbenzoylsinomenine . 245-246 + 39-3 14 24
C 2t H, 2 0,NCl from sinomenine and
ethyl chloroformate . 183 -108-4 7
/ +33-1 24 dil.HCl 22
Dihydrosinomenine 198 MeOH needles 1+193-6 25 CHCl, 5, 22
methiodide . . . . 268d. 5,22
oxime . . . . . 211d. 5, 22
semicarbazone . . . . 209d. 22
Methyldihydrosinomenine oil 31
hydrochloride-2H 2 O . 150 H2O + 35-1 14 H2O 31
semicarbazone . . . . 220 needles 31
1-bromodihydrosinomenine 237d. CHCl, prisms + 102-4 24 CHCI, 21, 32
hydrobromide . . . . 229-232 21
methiodide . . . . 225d. prisms 21
semicarbazone . . . . D. 250 MeOH prisms 21
1-benzerieazodihydrosinomenine 231 MeOH red prisms 36
1-aminodihydrosinomenine hydro-
chloride . . . . . > 300 36
5-(hydroxmethyl)-dihydrosino- 244 MeOH prisms + 73-0 29 MeOH 37
menine +
CHCl,
methiodide . . . . 205-220 MeOH S7
oxime 215-225 amorph. 37
Dihydrosinomenine methine . 173 Et 2 O prisms -84-3 18 CHCl3 45
Dihydrosinomenine dihydromethine. 133 Et 2 O prisms + 2-1 18 CHCl, 45
Desmethoxydihydrosinomenine 138 prisms + 59-2 23
hydrochloride '. + 48-9 23
( 231* 23
methiodide . . . . I 120
semicarbazone . . . . 235 23
Bis-8:8'-desmethoxydihydrosino-
mcnine . . . . . 304 prisms -24-5 23
1-bromodesmethoxydihydrosino- (190-198* 29
menine I 119 acetone prisms + 57-6 13 EtOH 33-34
methiodide . . . . 127d. H2O prisms 33-34
oxime . . . . . 236 prisms 33-34
1: l'-dibromobis-8:8'-desmethoxy-
dihydrosinomenino 227 acetone + 19-0 13 EtOH 33-34
dlhydrostnomonmo
moUiloclltlo 253-255 H2O prisms 33-84
oxlino . . . 287d. .. .. 33-84
Indloatoi raoomato with optical antlpoda.
SINOMENINE 361
Solvent
for Crystal Specific
Compound m.p. "G. recrystn. form rotation Temp. Solvent Refs.
Desmethoxydihydrosinomenine ( 158* 49
methine I 182 H2O + prisms -54-9 20 OHCl3 46
MeOH
Desmethoxydihydrosinomenine / 184* 49
dihydromethine I 156-5 Et 2 O prisms + 67-8 18 CHCI3 46
methiodide . . . . 226-229 MeOH prisms 46
/240-243* 49
Bis-1 :l'-desmethoxydihydrosino- prisms + 45-1 19 CHCl3+ 49
menine methine J 252
MeOH
methiodide . . . . amorph. 49
/245-248* 49
Bis-1: l'-desmethoxydihydrosino- 248-249 prisms + 33-2 20 CHCl3+ 49
menine dihydromethine MeOH
1-bromodesmethoxydihydrosino- /175-177* prisms* 47
menine dihydromethine I 192 MeOH prisms + 61-6 17 47
- hydrobromide . . . . 257 47
methiodide . . . . 273 47
1-bromodesmethoxydihydrosino- /189-192* 47
menine methine 1200-201 MeOH prisms -8-7 17 47
methiodide . . . . 243 H,0 47
Desmethoxydihydrosinomeninol-A
iH,0 138 + 45-1 23 24
Desmethoxydihydrosinomeninol-B . 158 24
methiodide . . . . 221-224 24
Sinomeninol . . . . 127 MeOH -23-7 28 CHCl3 22
methiodide . . . . 272 H2O prisms 22
Dihydrosinomeninol 162 MeOH prisms + 1-9 30 MeOH 22
methiodide . . . . 249d. plates -6-7 28 HjO 22
Desmethoxydesoxydihydrosino-
menine-iH 3 0 . . . . 148 plates 23
hydriodide . . . . 245 23
methiodide . . . . 267 23
1-bromodesmethoxydesoxydihydro-
sinomenine . . . . 127 acetone prisms + 40-4 12 EtOH 33-34
methiodide . . . . 253-255 33-34
Methyldesmethoxydesoxydihydro-
sinomenine . . . . oil 31
hydriodide-H 2 O 104-106 H2O needles 31
methiodide . . . . 257-258 31
Deamethoxydesoxydihydrosino- /133-136* 50
menine methine 1145-148 -65-2 19 49-50
Pesmethoxydesoxydihydrosino- /135-140 50
menine dihydromethine I 161 -77-9 19 49-50
1:9 ?-dibromodesmethoxydesoxy-
dihydrosinomenine dihydromethine 205d. MeOH 51-52
perbromide . . . . 112-113 51-52
Bis-1: l'-desmethoxydcsoxydihydro- /255-260* I 50
sinomenine 1230-237 benzene prisms + 91-6 20 EtOH
dihydrochloride 293-297 H2O 50
methiodide 275-279 Ha0 prisms 50
1-bromosinomeneine 217 EtOH prisms -88-0 9 CHCl3 53
hydrochloride . 231d. 53
hydrobromide . 229 53
methiodide 211-212 53
oxime 162 53
- oxime hydrochloride 280 53
1-bromodiacetylsinomeneme . 125-135 MeOH yellow + 8-8 20 CHCl3 59
prisms
1-bromosinomeneine methine . 187 MeOH prisms + 112-3 24 CHCl3 35
methiodide . . . . 213-214 35
1-bromodehydrometasinomenine
methine . . . . . 199-201 60
1-bromodesmethoxydihydrosino- / 190-5* MeOH prisms + 161-0 21 CHCl3 35
meneine I 206
hydrobromide . . . . 217 35
( + )-dihydrocodcinono . 163* BtOH + 207-4 26 CHCl3 35
193
oximo . . . . . 204-265 EtOH prisms 85
/IU-UO* prlntrn + 4-0 MoOU 29
(-I- Vdlliydrooodolnono mc Uiliii) 1 120 Ji
Indlontoi maomilto with optical nntlpodo.
362 SINOMENINE OH. X X V I
Solvent
for Crystal Specific
C
Compound m.p. C. recrystn. form rotation Temp. Solvent Sefs.
( + )-dihydrocodeinone dihydro- /113-116* Et 2 O + prisms + 50-0 11 MeOH 29
methine (. 93-97 EtOH
l-bromo-(+)-dihydrocodeinone 148* . +7-0 11 MeOH 29
methine 130
methiodide . . . . 278-279 29
/ 105* + 146-4 30 EtOH 56-57
( + )-dihydrocodeino (anhyd.) . I 110
( + )-dlhydrocodeine 2H2O 87-88 56-57
/ 257* MeOH + 80-1 30 H2O 56-57
methiodide . . . . I 257
EtOH
( + )-dihydromorphine 154* + 151-5 29 EtOH 56-57
159
hydriodide . . . . 261* + 87-9 29 H2O 56-57
methiodide . . . . 267 + 74-9 31 H2O 56-57
f 146* + 177-2 28 56-57
( + )-6-chlorodihydrocodide I 173
/ 253* MeOH + 114-8 7 H2O 56-57
methiodide . . . . I 248
/ 85* + 179-6 20 57
( + )-desoxycodoine-0 I 103
/ 218* MeOH + 102-4 13 67
methiodide . . . . I 238
(+)-7-hydroxydihydrocodeitie . 225 58
Sinomenine hydrate 139(160) prisms + 40-8 26 OHOl3 61, 53
methiodide . . . . 192-195 53
dioxime . . . . . 231d. 61
disemicarbazone 191d. 61
1-bromosinomeninone 227d. MeOH prisms + 54-5 16 EtOH 63
methiodide . . . . 244-246 H2O 63
semicarbazone . . . . D. 118 63
mono-imide . . . . 300 prisms + 110-2 16 OHCl3 63
mono-imide oxime D. 300 63
monoxime. . . . . 199 needles 63
dioxime . . . . . c. 189 d. prisms 63
1:5:8-tribromosinomeninono hydro-
bromide . . . . . 235 prisms 69
Methylsinomeninone 188 MoOH prisms + 18-7 14 OHOl8 66
methiodide . . . . D.225-227 prisms 66
oxime . . . . . c. 170 66
1-bromomethylsinomenmone . 110 44
Sinomeninone furazan 223-225 MeOH prisms + 136-2 48
methiodide . . . . 218-220 MeOH prisms 48
1-bromosinomeninone furazan D. 262 prisms 51-52
Sinomeninone furazan methine 226-227 MeOH prisms + 49-9 19 48
methiodide . . . . not cryst. 48
Sinomeninone furazan dihydromethine 205-207 MeOH prisms + 21-9 19 48
1-bromosinomeninone furazan
methine . . . . . 225d. prisms 51-52
1: D ?-dibromosinomeninone furazan
methine . . . . . D. 212 MeOH prisms 51-52
1-bromosinomeninone furazan dihy-
dromethine . . . . 221-223 acetone prisms 51-25
hydrobromide . . . . 259 H2O needles 51-52
1:9:10-tribromosinomeninone fura-
zan dihydromethine . D. 146 51-52
( )-thebenone . . . . 120*,134 EtOH prisms -78-6 18 OHOl3 49, 46
oxime . . . . . 204-5 MeOH prisms 46
/250-254* CHCl3+
bis-1: l'-( J-thebenone . 1230-233 -163-3 20 MeOH 49
( )-thebenone ketone . 187 MeOH prisms 48
dioxime . . . . . D.225-260 MeOH 48
isonitroso-( )-thebenone D. 165 48
oxime . . . . . 241-242 MeOH 48
7-mcthoxy-( )-thebenone 128 Et 2 O prisms -147-7 18 CHCl3 45
oxime . . . . . 168 EtOAc plates 45
isonitroso-derivative . resin 45
/ 158* 49
9:10-dohydro-( )-thebcnono . I 113 prisms -206-0 18 OHCl, 46
/202-205 prisms -201-9 20 CHCl,+ } 49
IJIH- I: I'-I): IO-dohydro-( J-tlrobononn 1208-212 MeOIl
* ludtavtos woomuto with optical anUpodo.
CH. x x v i SINOMENINE 363
Solvent
for Crystal Specific
Compound m.p. 0C. recrystn. form rotation TenVp. Solvent Refs.
MeOH 47
l-bromo-9:10-deliydro-()-thebenone /159-162*
I 145 MeOH prisms -186-8 11 CHCl3 47
9?-bromo-9:10-dehydro-()-thebenone /156-158* -113-3 17 acetone
47
1125-133 47
7-methoxy-9:10-dehydro-( - )-the-
benone . . . . . 118 Et 2 O prisms -286-0 13 CHCl3 45
oxime . . . . . 180d. BtOH prisms 45
( )-thebenone ketone furazan. 148 MeOH -120-4 1) 48
l-bromo-()-thebenone ketone furazan 202-203 51-52
9:10-dehydro-( )-thebenone ketone
furazan . . . . . 197 MeOH prisms -485-2 1) 48
l-bromo-9:10-dehydro-( )-theben-
one ketone furazan 191 51-52
9 ?-bromo-9:10-dehydro-( )-theben-
one ketone furazan 152-153 acetone plates 51-52
1:9 ?-dibromo-9:10-dehydro-( - )-
thebenone ketone furazan 210-211 prisms 51-52
( )-thebenane . . . . 48-54 -3-14 11 48, 50
9:10-dehydro-( )-thebenane . 107-112 -175-7 13 48, 50
<*-dihydrosinomeninone . 128 MeOH prisms + 64-8 25 CHCl3 61,70
methiodide . . . . 284d. MeOH prisms 61,70
oxime . . . . . 170d. HaO prisms 61, 70
phenylhydrazone 146 61
semicarbazone . . . . 191d. 61
Dibenzoyl-a-dihydrosmomeninone . 141 MeOH prisms 70
/3-dihydrosinomeninone . 104 MeOH needles + 95-2 2B CHCl3 61, 70
methiodide . . . . 281d.
/anhyd. 145-150 \
oxime . . . J 107 H1O 70
80 MeOH needles ) -
semicarbazone . . . . 206d.
1-bromodihydrosinomeninone . 231 BtOH prisms 66
Dihydromethylsinomeninone . 128 33% prisms + 71-1 15 CHCl3 66
MeOH
methiodide . . . . 248 MeOH needles 66
m o n o x i m e . . . . . 117 MeOH 66
( + )-7-hydroxydihydrothebainol 58
( + Hetrahydrosinomenmoiie 157 58
( + )-l-bromotetrahydrosinomeninone 136 58
' Diacetyl-1-bromodehydro-
sinomenine' . . . . 203 72
methiodide . . . . 204 72
' Dimethyl-1-bromodchydro-
sinomenine' methiodide 201-5 72
Sinomeninic acid . . . . 291d. prisms + 88-9 18 H3O 73
hydrochloride . . . . 278-280 plates + 81-0 18 H1O 73
methiodide . . . . 239 MeOH prisms + 61-8 18 H1O 73
1-bromosinomeninic acid 251 prisms + 70-3 18 H3O 73
hydrochloride . . . . 292d. plates 73
hydrobromide . . . . 306d. plates + 54-8 18 H1O 73
methiodide . . . . 276d. prisms + 49-7 20 H1O 73
Methylsinomeninic acid . 295 prisms + 12-4 18 H1O 73
barium salt D. > 300 73
imide . . . . . 239-241 75
1-bromomethylsinomeninic acid 271 44
1-bromosinomeneinic acid 261-262 prisms + 34-6 18 H1O 73
methiodide . . . . D. 249 H1O + 45-8 18 H1O 73
barium salt . . . . D. > 300 73
1-bromosinomenilic acid . 285 MeOH prisms 69
ethyl ester . . . . 62 BtOH prisms 69
methiodide . . . . D. > 180 H2O prisms 69
barium salt . . . . >295 EtOH prisms 69
Benzoyl-1 -bromosinomenilic acid 267 MeOH prisms 69
Acetyl-1-bromosinomenilic acid 265 BtOH prisms 69
l:7-dibromoBinomenilic acid . 225 dil.HOAc prisms 69
methiodido . . . . 2 ISd. H1O prisms 69
barium unit . . . . 2I8-28M. H1O rosottos 09
methyl outer liydrochlorlclo . 200-212 prisms 0
~ othyl onUir . . . . 89 11,0 + prlmriB 09
WtOII
* JlHlldiiitix riKioimilo WlUi optical uuUpodo,
364 SINOMENINE OH. X X V I
Solvent
for Crystal Specific
Compound m.p. 0. recrystn. form rotation Temp. Solvent Befs.
l:7-dibromosinomeniIic acid ethyl
ester hydrochloride 234-236 EtOH prisms 69
Sinomenilone. . 176 BtOH prisms + 442-1 24 CHCl3 76
oxime . 238 polygons 76
1-bromosinomenilone 179 needles + 248-3 22 EtOH 69
methiodide . . . . 220 H1O needles 69
oxime . . . . . 27Od. Bt 3 O prisms 69
Dihydrosinomenilone 132 acetone + 207-8 24 CHCl3 76
methiodide . . . . D.220-240 prisms 76
oxime . 155-156 76
1-bromodihydrosinomenilone . 224 EtOH prisms 76
methiodide . . . . 22Od. 76
oxime . . . . . 222 EtOH 76
oxime hydrochloride . 280 76
Benzoyl-1-bromodihydrosinomenilone 180 prisms 76
Dihydrosinomenilone methine . 220 EtOH plates + 18-6 24 CHCl3 76
Dihydrosinomenilone dihydro-
methine . . . . . 175 acetone plates -24-6 24 CHCl3 76
Anhydrobis-sinomelone . 266 EtOH prisms -522-7 24 CHCl3 76
Anhydrobis-dihydrosinomelone 247 EtOH prisms 76
6:6-dichlorodihydro8inomenilan 110-116 MeOH prisms 77
Dihydrosinomenilan 145-150 acetone plates + 34-2 28 EtOH 77
methiodide . . . . 85-87 H,0 77
Dihydrosinomenilan methine . 183-185 EtOH prisms -98-2 28 EtOH 77
methiodide . . . . 225-227 H3O prisms 77
Dihydrosinomenilan dihydromethine 143-146 acetone prisms + 45-6 28 EtOH 77
methiodide . . . . amorph. 77
Sinomelan . . . . . 85-90 Et,0 prisms -178-0 28 EtOH 77
Dihydrosinomelan . . . . 55 Et0 prisms -104-6 28 EtOH 77
Bis-desmethoxysinomenylidene > 312 prisms 23
hydrochloride . . . . + 335-5 23
methiodide . . . . >300 23
dioxime . . . . > 300 23
monosemicarbazone . > 300 23
Dlsmomenine . . . . 222 MoOH plates + 150-0 78
hydrochloride . . . . > 290 H2O 78
methiodide . . . . 263d. H,0 prisms 78
oxime . . . . . 265d. 78
semicarbazone . . . . >290 78
(A-disinomenine . . . . 228 MeOH needles -127-0 78
hydrochloride . . . . > 290 78
methiodide . . . . 267-268 Hsb polyhedra 78
oxime . . . . . >280 78
somicarbazone . . . . >290 .. 78
If ully aromatic degradation products; see Chap. I CXVIII
llamibanonine . . . . 116 MeOH prisms -219-5 25 EtOH 90
hydrobromide . . . . 207-208 MeOH rhombs. -169-6 26 CHCl, 90
- - u l t r a to 222d. MeOH prisms 90
-nitrite 214 90
ploiato 210 MeOH prisms 90
mothiodido . . . . 177-178 MeOH plates 90
oxime . . . . . 141-142 90
oxime hydrochloride . 242-243 90
mothine base . . . . 158 benzene needles 90
methine base methiodide notcryst. 90
acotylated methine base methiodide 230d. MeOH prisms 90
B I B L I O G R A P H Y TO C H A P T E R XXVI
1. ISTIIWAKI, Chugai Iji Shimpo, 1920, 6. K O N D O , OOHIAI, and NAKAJIMA, J.
959, 1. Pharm. Soc. Japan, 1923, 497, 511.
2. L i u and L o , Pharm. Chem. Pes. Eepts. 7. OOHIAI, ibid., 1924, 5 0 3 , 8.
(Ohina), 1935, 1, No. 1, 13. 8. GrDAmsB,,Areh.Pharm.,1921,259,135.
3. M A , and Li, ibid., 29. 9. G O T O , Proc. Imp. Acad. (Tokyo), 1926,
A. K U B O T A , Ber. g&s. Physiol, exptl. 2,7.
Pharmalcol., 87, 461. 10. J. Agr. Soc. Japan, 1926, 2, 17.
0. CJOTO, J. Oham, Soc. Japan, 1023, 44, 11. Proe. Imp. Acad. (Tokyo), 1926,
7OC. 2, 414.
OH. XXVI SINOMENINE 365
12. GOTO a n d SUDZUKI, Bull. C'hem. Soc. 45. GOTO a n d SHISHIDO, Bull. Chem. Soc.
Japan, 1929, 4 , 163. Japan, 1931, 6, 229.
13. K O N D O a n d OOHIAI, J. Pharm. Soc. 46. INABA, and SHISHIDO, Ann.,
Japan, 1927, 539, 17. 1931, 485, 247.
14. Ann., 1929, 470, 224. 47. OGAWA, a n d SAITO, Bull. Chem.
15. GOTO a n d SHISHIDO, Bull. Chem. Soc. Soc. Japan, 1935, 10, 481.
Japan, 1941, 16, 170. 48. and MITSUI, ibid., 1931, 6, 197.
16. B E N T L E Y and ROBINSON, J.O.S., 49. MIOHINAKA, and SHISHIDO, Ann.,
1952, 947. 1935, 515, 297.
17. GOTO, Proc. Imp. Acad. (Tokyo), 1926, 50. and SHISHIDO, Bull. Chem. Soc.
2, 167. Japan, 1935, 10, 252.
18. OOHIAI a n d K O N D O , J. Pharm. Soc. 51. and MITSUI, ibid., 1932, 7, 223.
Japan, 1926, 538, 99. 52. J. Chem. Soc. Japan, 1932,
19. K O N D O a n d OOHIAI, ibid., 1927, 549, 53, 737.
913. 53. and NAMBO, Bull. Chem. Soc.
20. GOTO, Bull. Chem. Soc. Japan, 1929, Japan, 1930, 5 , 165.
4, 103. 54. SOHOPF a n d P F E I F K E B , Ann., 1930,
21. and NAKAMUBA, ibid., 195. 4 8 3 , 157.
22. and MITSUI, ibid., 1930, 5, 282. 55. GOTO, SHISHIDO, a n d TAKUBO, ibid.,
23. and SUDZUKI, ibid., 1929, 4 , 244. 1932, 497, 289.
24. OOHIAI and HAKOZAKI, J. Pharm. Soc. 56. Proc. Imp. Acad. (Tokyo), 1940,
Japan, 1930, 50, 360. 16, 403.
25. ibid., 1929,49, 91. 57. a n d A B A I , Ann., 1941, 547, 194.
26. S P E Y E R and S I E B E B T , Ber., 1921, 54, 58. Bull. Chem. Soc. Japan,
1519. 1942, 17, 113; Chem. Abs., 1947,41,
27. GOTO a n d OGAWA, Ann., 1934,511,202. 4502.
28. SKITA, NOBD, REIOHERT, and 59. and SHISHIDO, Bull. Chem. Soc.
STUKABT, Ber., 1921, 54, 1560. Japan, 1933, 8, 366.
29. GOTO and SHISHIDO, Bull. Chem. Soc. 60. A B A I , and ODEBA, ibid., 1942,17,
Japan, 1935, 10, 597. 393; Chem. Abs., 1947, 4 1 , 4502.
30. a n d MITSUI, ibid., 1931, 6, 33. 61. and SUDZUKI, Bull. Chem. Soc.
31. K O N D O a n d OOHIAI, Ber., 1930, 6 3 , Japan, 1929, 4, 271.
646. 62. VON PEOHMANN, Ber., 1888, 2 1 , 1411.
32. SMALL a n d COHEN, J.A.C.S., 1932,54, 63. GOTO a n d NAMBO, Bull. Chem. Soc.
802. Japan, 1930, 5, 73.
33. GOTO a n d INABA, Bull. Chem. Soc. 64. SCHOPJ", P F E I T K B B , a n d H I B S O H , Ann.,
Japan, 1930, 5, 93. 1932, 492, 213.
34. J. Chem. Soc. Japan,
1930, 65. W A I L A O H , ibid., 1918, 414, 296.
5 1 , 58. 66. GOTO, NAMBO, and INABA, Bull. Chem.
35. Ann., 1931, 489, 86. Soc. Japan, 1930, 5, 223.
36. a n d SHISHIDO, Bull. Chem. Soc. 67. KITASATO a n d GOTO, Ber., 1930, 6 3 ,
Japan, 1930, 5, 311. 2696.
37. a n d INABA, ibid., 315. 68. GOTO a n d KITASATO, J. Chem. Soc.
38. ibid., 1931,6, 79. Japan, 1931, 52, 162.
39. B E N T L E Y , ROBINSON, and WAIN, 69. SHISHIDO, a n d TAKUBO, Ann.,
J.C.S., 1952, 958. 1932, 495, 122.
40. GOTO a n d TAKUBO, Bull. Chem. Soc. 70. and SHIBASAKI, ibid., 1933, 503,
Japan, 1931,6, 126. 277.
41. A B A I , and ODEBA, ibid., 1943,18, 7 1 . SOHOPF a n d H I B S C H , ibid., 1931, 489,
116; Chem. Abs., 1947, 4 1 , 4503. 224.
42. and NAGAI, Bull. Chem. Soc. 72. GOTO, M O B I , and A B A I , Bull. Chem.
Japan, 1943, 18, 143; Chem. Abs., Soc. Japan, 1942, 17, 439; Chem.
1947, 4 1 , 4503. Abs., 1947, 4 1 , 4503.
43. a n d NAOAI, Bull. Chem. Soc. 73. TAKUBO, a n d M I T S U I , Ann.,
Japan, 1943, 18, 218; Chem. Abs., 1932, 494, 1.
1947,41,4504. 74. and SHISHIDO, ibid., 1933,501,304.
44. and ABAI, Bull. OMm. Soc. 75. and Mioin, Bull. Chem. Soo.
Japan, 1042, 17, 304 ; Cham. Abs., Japan, 1044, 19, 140; Cham. Abs.,
1047,41, 4502. 1047,41,4003.
366 SINOMENINE
76. GOTO a n d TAKTJBO, Ann., 1932, 499, 84. KBETTGER, E D D Y , and STJMWALT, U.S.
169. Pub. Health Service Suppl., 1941,
77. and SHISHIDO, ibid., 1933, 507, 165, 1.
296. 85. - i b i d . 1943, 813.
78. and STTDZUKI, Bull. Chem. Soc. 86. R O B I N S O N and STJGASAWA, J.G.S.,
Japan, 1929, 4, 107. 1931, 3163.
79. K O N D O a n d OOHIAI, J. Pharm. Soc. 87. ibid., 1933, 280.
Japan, 1927, 549, 923. 88. D E C K E R and EIOHLER, Ann., 1913,
80. GOTO, Bull. Chem. Soc. Japan, 1929, 395, 377.
4, 129. 89. ROBINSON, J.O.S., 1936, 1079.
81. KITASATO, Acta Phytochim., 1927, 3 , 90. K O N D O , SATOMI, and ODEBA, Ann.
175. Rep. Itsuu Lab., 1951, 2, 35.
82. OCHIAI a n d K O N D O , J. Pharm. Soc. 91. J. Pharm. Soc. Japan, 1938, 5 8 ,
Japan, 1929, 49, 425. 46.
83. TAKAOBI, Deut. Med. Wochschr., 1936, 92. Ann. Rep. Itsuu Lab., 1950,1, 50.
62, 1634.
XXVII
D E R I V A T I V E S OF P H E N A N T H R E N E
O B T A I N E D BY D E G R A D A T I O N OF T H E
MORPHINE ALKALOIDS
MANY degradations of alkaloids of the morphine group proceed with
extrusion of the whole of the nitrogen-containing side-chain and pro-
duction of a fully aromatic phenanthrene derivative. These reactions
are of great value in the study of the constitutions of the alkaloids, as
the readily determined positions of the substituents in the resulting
aromatic compound indicates the nature of the basic alkaloid structure,
and the ready extrusion of the basic side-chain led Gulland and Robin-
son to advance the now-accepted and proved mode of attachment of
this chain to the hydrogenated phenanthrene skeleton in morphine and
related bases.
Such degradations may be achieved in several ways, namely by heat-
ing the base or its quaternary salt with acetic anhydride, hydrochloric
acid, or sodium ethoxide and ethyl alcohol at temperatures above
130-160 C. or by Hofmann's exhaustive methylation method.
Extrusion of the side-chain is never observed independently of the
formation of a fully aromatic phenanthrene derivative, and always
accompanies the formation of the latter except in the degradation of
apomorphine, morphothebaine, isothebaine, and thebenine, bases that
are known not to contain the typical morphine skeleton.
These important phenanthrene derivatives are conveniently con-
sidered together. They can be divided into five groups, namely:
(a) Derivatives of 3-hydroxy-4:5-phenanthrylene oxide;
(6) Derivatives of 3:4-dihydroxyphenanthrene;
(c) Derivatives of 3:4:6-trihydroxyphenanthrene;
(d) Derivatives of 3:4:8-trihydroxyphenanthrene;
(e) Derivatives of 3:4:6:7-tetrahydroxyphenanthrene;
and they will be discussed in t h a t order.
D E R I V A T I V E S OF 3 - H Y D R O X Y - 4 : 5 - P H E N A N T H R Y -
L E N E O X I D E ( M O R P H E N O L ) [i]
Hofmann degradation of codeine [n] methiodide affords a-codei-
methine [ni] [2-3], which can be isomerized to /3-codeimethine [iv]
[4-6], and further degradation of these bases by Hofmann's method
yields methylmorphonol [v] [7-9], the degradation being best effected
by boating tho mothino mothornofchylsulphates with sodium ethoxide in
368 DERIVATIVES OF PHENANTHRENE OH. X X V I I
D E R I V A T I V E S OE 3 : 4 - D I H Y D R O X Y P H E N A N -
T H R E N E (MORPHOL) [xxi]
Acid-degradation of many of the morphine bases and their quaternary
salts, and degradation by heating with sodium ethoxide and ethyl
alcohol at 160 C, results in opening of the cyclic ether link and the
production of phenanthrene derivatives having a substituted or free
hydroxyl group at C-4.
When morphine methiodide is heated with acetic anhydride and
sodium acetate, diacetylmorphol [XXII] is obtained [29], and this com-
pound is also obtained in the same way from a-isomorphine [3O].
Morphol [xxi] is produood by the hydrolysis of [xxn] [29] and also from
OH. XXViI DERIVATIVES OF 3:4-DIHYDB0XYPHENANTHBENE 371
heating a-codeimethine [in] with hydrogen chloride at 180 C, the other
products of this degradation being methyl chloride, /3-dimethylamino-
ethanol, and /3-codeimethine [rv], which is more stable than the a-
isomer [4].
MOBPHOL
Morphol [xxi] is a readily oxidizable phenol that will reduce ferric
chloride and Fehling's solution [29], It can be oxidized to 3:4-phenan-
threne quinone [xxin] by silver oxide, the reverse change being effected
by sulphur dioxide [31-33]. Morphol itself has been synthesized by
heating the aldehyde [xxiv] (prepared by the Gattermann method from
3-hydroxyphenanthrene [34]) with pyridine, hydrogen peroxide, and
potassium hydroxide under hydrogen [31], and the quinone has been
synthesized by coupling 3-hydroxyphenanthrene with a diazonium salt
and reducing the resulting azo-compound to 3-hydroxy-4-aminophenan-
threne followed by oxidation of the latter [32-33].
Diacetylmorphol [xxn] may be oxidized with chromic acid to
diacetylmorpholquinone [xxv, E. = Ac] without loss of groups [29,
35], and the latter may be hydrolysed to morphol-9:10-quinone [xxv,
R = H], the monomethyl ether of which (see below) can be further
oxidized to phthalonic and phthalic acids [36], showing that both
hydroxyl groups of morphol-9:10-quinone are in the same aromatic
nucleus. That the hydroxyl groups are adjacent is indicated by the
facts that whereas morphol-9:10-quinone is an excellent mordant dye
[35] its monomethyl ether is not [32]; analogy for this is to be found
in the behaviour of other orthodihydroxycompounds.
ryv0s)
O^
c< v ")
NMe2
H
[XXXIII] [XXXIV] [XXXV]
NMe 2
[XL]
MeO MeO
OAc 0
NMe2
HO
[XLIV] [XLV] [XLVI] [XLVII]
DERIVATIVES OF
3:4:6-TRIHYDROXYPHENANTHRENE
Whereas derivatives of codeine and morphine must undergo dehydra-
tion and loss of the hydroxyl group at C-6 for aromatization to occur,
thebaine and codeinone can be degraded to aromatic compounds with
retention of the oxygen substituent at 0-6.
3-Methoxy-4:6-diacetoxyphenanthrene [Li] is formed when
codeinone [Ln] [68] and sinomenine hydrate [Lm] [69] are heated with
acetic anhydride and sodium acetate; a second product in the degrada-
tion of [Lm] is triacetyHsothebenine [LIV?]. The 1-bromo-derivative
can be obtained in like manner from the antipodes of 1-bromosino-
meninone [69-70] and reduced catalytically to [LI]. Hydrolysis of
[LI] affords the corresponding 4:6-dihydroxy-compound, which results
from heating codeinone methiodide with ethanol at 160 C. [71]; both
compounds have been identified by conversion to 3:4:6-trimethoxy-
phenanthrene [68].
X)OOH
MeO MeO
MeO CHiCH2(J)
NMe
VzCH 2 -CH 2
MeO MeO
[LXII]
DERIVATIVES OF
3:4:8-TRIHYDROXYPHENANTHRENE
3-Methoxy-4:8-diacetoxyphenanthrene [LXXXIII]. /MMmethyl-
aminoethanol and [LXXXIII] are formed when i/t-codeinone [LXXXIV] is
heated with acetic anhydride, but the main product of this reaction is
triacetylthebenine [LXXXV, R = Ac] [89]. ^r-Codeinone methiodide and
ethanol at 1600. give 3-methoxy-4:8-dihydroxyphenanthrene [89-
90], which on methylation affords 3:4:8-trimethoxyphenanthrene [90],
identical with an authentic specimen prepared in the usual way from
2-nitroveratric aldehyde and 2-methoxyphenylacetic acid [67]. In this
way the location of the hydroxyl group in i/f-codeine and allo-i/r-codeine,
at C-8, was proved.
Bromination of e-codeimethine methyl ether [vn, R = Me] affords
bromohydroxydihydro-e-codeimethine methyl ether, which on acetolysis
gives 3:8-dimethoxy-4-acetoxyphenanthrene [85].
3:4:8-Trimethoxy-5-vinylphenanthrene. Thebenine [LXXXV,
R = H], itself a fully aromatic phenanthrene derivative, can be de-
graded to 3:4:8-trimethoxy-5-vmylphenanthrene [LXXXVI] [91-92],
OH. XXVIi D E R I V A T I V E S OE 3 : 4 : 8 - T R I H Y D R 0 X Y P H E N A N T H R E N E 381
MeO- MeO-
MeO-
CH2=OH^
CH:
OMe
[LXXXVI] [LXXXVII] [LXXXVIII]
DERIVATIVES OF
3:4:6:7-TETRAHYDROXYPHENANTHRENE
These are all obtained b y the degradation of derivatives of sinomen-
ine [LXXXIX] by methods similar to those used in the morphine-thebaine
series.
3 : 7 - D i m e t h o x y - 4 : 6 - d i h y d r o x y p h e n a n t h r e n e (sinomenol) [xc]
is obtained when sinomenine [LXXXIX] [98-99], and when the three
sinomenine methines, [xci], [xon], and [XCIII] [100], are boiled with
66 per cent, potassium hydroxide. I t gives a dimethyl ether [dimethyl-
sinomenol] [98], also accessible from sinomenine methyl ether [101],
and a dibenzoyl-derivative [98], which also results when sinomenine or
the achro-methine [xci] is heated with benzoic anhydride a t 160 O.
[100-102].
OMe OMe
[XOVII] [XCVIII] [XCIX] [C]
is boiled with alkali and methyl sulphate these two dimolecular deriva-
tives, [ox, R = H] and [ox, R == Mo], are obtained in varying amounts
CH. XXVIi D E R I V A T I V E S OF 3 : 4 : 6 : 7 - T E T R A H Y D R O X Y P H E N A N T O : R E N E 385
T H E B A S I C P R O D U C T S OP D E G R A D A T I O N
The basic side-chain on extrusion appears in various forms according
to the nature of the degradation, as follows:
(a) Ethylene and trimethylamine during exhaustive methylation;
(6) /J-methylamino- or /J-dimethylaminoethanol, or their acetyl esters,
during the acetolysis of the cyclic bases or their methiodides;
(c) /3-dimethylaminoethyl ethyl ether during degradations with
sodium ethoxide and ethyl alcohol;
(d) tetramethylethylenediamine during degradations with hydro-
chloric acid or in which the latter is liberated.
I t has been suggested by Knorr that the initial basic product in each
degradation (except exhaustive methylation) is vinyldimethylamine,
C H 2 = C H - N M e 2 (or vinylmethylamine, CH 2 =CH-NHMe), which is
subsequently converted to AcO CH 2 CH 2 NMe 2 , EtO CH 2 CH 2 NMe 2 ,
and Cl CH 2 CH 2 NMe 2 by the addition of acetic acid, ethanol, and
hydrogen chloride respectively [71]. /3-Dimethylaminoethyl chloride
readily polymerizes to the piperazine salt [cxxx], which is decomposed
by alkalis to tetramethylethylenediamine, acetylene, and j3-dimethyl-
aminoethanol [119].
MISCELLANEOUS DEGRADATIONS
The distillation of morphine with zinc-dust affords phenanthrene
[123-4] together with ammonia, trimethylamine, pyrroline, pyridine,
quinoline [123], and 'morphidine' [118], which is a mixture of two bases
C 17 H 15 N and C 17 H 13 N presumably of the phenanthridine type [125].
Thebaine on distillation with zinc-dust gives pyrene [cxxxni], also ob-
tained b y t h e action of hydriodic acid and red phosphorus on t h e
alkaloid [126]. Thebenidine [cxxxiv] is also produced during the
zinc-dust distillation of thebaine [123]. I t has been synthesized b y
heating 4-formamidophenanthrene with phosphorus pentoxide in
xylene [127].
Solvent
for Crystal
6
Compound m.p. C recrystn. form Refs.
Morphenol . . . . . . . 145 E t 2 O or noodles 14,17,19,
EtOH 18, 20
Acetylmorphenol . . . . . 140 needles 14, 24
Benzoylmorphenol . . . . . 123 HOAo 14, 21
Acetylbromomorphenol . . . . . 208 needles 15
Methylmorphenol . . . . . 65 EtOH 9-11, 7, 8
1-bromomethylmorphenol . . . . 118-5-119-5 10, 14-15,
16
oxidation product (C 1 Q H 7 0 2 Br 2 ) 2 0 > 330 ^.NO 2 15
j8-bromomothylmorphenol . . . . 124 needles 15
Ethylmorphonol . . . . . 59 17
1-acetylmethylmorphenol . . . . 140-5 EtOAc 54
6-methylmorphenol methyl ether 89-90 MeOH prisms 128
picrate . . . . . . . 138-5-139-5 MeOH red prisms 128
Morphol . . . . . . . 143 petrol 29, 31-32
Morphol- 3:4-quinone (3:4-phenanthrene- 133d. benzene-(- red 32
quinone) petrol needles
Morphol-9:10-quinone . . . . . EtOH brown 23
needles
Diaeetylmorphol . . . . . 159 needles 29-30
Diacetylmorpholquinone . . . . 196 HOAo yellow 23, 29
noedlos
azine . . . . . . . 215-218 23
3-Mothylmorphol . . . . . 02-03 noodles 20, 41-42
- plomto . . . . . . . 150
OH. X X V I I D E R I V A T I V E S OF P H E N A N T H R E N E 380
Solvent
for Crystal
0
Compound m.p. O. recrystn. form Eefs.
3-methyl-4-acetylmorphol . . . . 131 BtOH needlea 7, 19, 29
38-39
3-methyl-4-acetylmorpholquinone . 205-207 HOAo yellow 22-24
needlea
3-methyI-4-benzoylmorphol . . . . not cryst. 22
3-methyl-4-benzoylmorpholquinone 228 yellow 22
needles
Dimethylmorphol . . . . . 44 MeOH 44-45
pierate . . . . . . . 104-105 44-45
dibromo-derivative . . . . 125 44-45
3-methyl-4-(;8-dimethylaminoethyI) -morphol n o t cryst. 52
hydrochloride . . . . . 214-215 52
pierate . . . . . . . 189 52
methiodide . . . . . . 196-198 52
C 166 MeOH needles 48
l-bromo-3.methylmorphol . . . . { 141-5- petrol rods 16
{ 142-5
1-bromodimethylmorphol . . . . oil 16
pierate . . . . . . . 113-114 EtOH red 16
needles
s t y p h n a t e . . . . . . 105-108 EtOH red 16
needles
l-bromo-3-methyl-4-acetyImorphol . 163-165-5 16
l-aoetyl-3-methylmorphol . . . . 161-162 needles 53
semicarbazone . . . . . 220 53
l-diacetylamino-3-methyl-4-acetylmorphol 178-179 Et2O needles 55-56
Bis-diacetylmorphol . . . . . 255 H2O + prisms 57
HOAe
Bis-[3:4-dimethylmorphoI] . . . . 222 EtOH+ prisms 57
EtOAe
Bis-1: l'-[3-methyl-4-acetylmorphol] 237 HOAo needles 57
3-methoxy-4:9 (or 10)-diacetoxyphenanthrene 201 EtOH 58
3:4:5-trihydroxyphenanthrene 148 H2O 25
3 : 4 : 5-triaoetoxyphenanthrene not cryst. 25
3 : 4 : 5-triacetoxyphenanthrenoquinono not cryst. 25
azine . . . . . . . cryst. 25
3:4:5-trimethoxyphenanthrene oil 25
pierate . . . . . . . 166 leaflets 25
3:4:6-triacetoxyphenanthrone 165-167 EtOH 82-83
l-bromo-3:4:6-triacetoxyphenanthreno 216 83
3-methoxy-4:6-diacetoxyphenanthrene 102-163 HOAo 68
l-bromo-3-methoxy-4:6-diacetoxyphenan-
threne . . . . . . . 162 69
3-methoxy-4:6-dihydroxyphenanthrene 71
3:4-dimethoxy-4-hydroxyphenanthrene
(thebaol) . . . . . . 93-94 EtOH prisma 71, 72-3
Thebaolquinone . . . . . . 233 HOAo 72-73
azine with o-tolylenediamine 192 72
Acetylthebaol . . . . . . 122 EtOH prisms 72, 78
Dibromoacetylthebaol . . . . . 179 HOAc plates 73
Acetylthebaolquinone . . . . . 205 HOAc yellow 72, 78
needles
azine w i t h o-phenyl enediamme . 265 <N02 prisms 78
azine with o-tolylenediamine 201-203 72
Bromoaeetylthebaolquinone 310 ^NO2 needles 73
Benzoylthebaol . . . . . . 160-161 H2O + needles 74
HOAo
D i b r o m o b o n z o y l t h o b a o l . . . . . 229 74
Bonzoylthebaolquinono , , . . . 216 74
4-(jS-dimoUiyluminool)l)yl)-lholiiit)l . oil 43
piomto . . . . . . . 180 i;t
moUiladlilti . . . . . . 1UU-200 <i:i
390 DERIVATIVES OF PHENANTHRENE OH. XXVII
Solvent
for Crystal
Compound m.p. 0. recrystn. form Befs.
3:4:6-trimethoxyphenarithrene oil 80, 76, 79
picrate . . . . . . . 108-109 BtOH 80, 76, 79
6-acetoxy-5:5'-dimethoxydiphenic acid . 229 H2O + needles 78
BtOH
6-hydroxy-5:5'-dimethoxydiphenic acid . 172 and 50% prisms 78
235 BtOH
5:6:5'-trimethoxydiphenio acid 215 H2O + prisms 78
MeOH
1:5:6-trimethoxyfluorenone-4-oarboxylio acid 256 H2O + yellow 78
HOAo needles
2:4-dinitrophenylhydrazone 286 amorph. 78
8:3-dimethoxy-3:4-benzocoumarin 148-149 EtOH noedles 78
4'-hydroxy-6:3'-dimethoxy-3:4-benzocoumarin 172 BtOH prisms 78
4'-acetoxy-6:3'-dimethoxy-3:4-benzocoumarin 192 EtOH needles 78
5 : 6 : 2 ' : 5'-tetramethoxydiphenyl-2-carboxylic 78
acid . . . . . . . 162-5 EtOH needles
1:4:5:6-tetramethoxyfluorenone 183 EtOH prisms 78
2:4-dinitrophenylhydrazone 290 NOa needles 78
1:6-dihydroxy-4:5-dimethoxyfluorenone ? 147 EtOH needles 78
2:4-dinitrophenylhydrazone 285 HOAo 78
3:6-dimethoxyphenanthrene-1:4-quinone 223 HOAc needles 78
2-hydroxy-3:4-(7'-methoxynaphtho-l': 2')-
phenazine . . . . . . 295-297 needles 78
8-carboxy-7-(/3-carboxyvinyl)-2-methoxy-l: 4- 273-275 50% prisms 78
naphthoquinone BtOH
3-methoxy-4:8-diacetoxyphenanthrene 155-156 89-90
3:8-dimethoxy-4-acetoxyphenanthrene 196 MeOH 85
3:4:8-trimethoxyphenanthrene 136-137 EtOH plates 90
picrate . . . . . . . 127-129 needles 90
dibromide . . . . . . 140-142 HOAo needles 90
3-methoxy-5-methyl-5-phenanthro-[4:5 bcd]-
p y r a n [LXXXVIII, R = Me] 118-5 BtOAc 97
picrate . . . . . . . 107-108 EtOH purple 97
rods
1-bromo-derivative . . . . . 104-105 subl. needles 97
3-hydroxy-5-methyl-5-phenanthro-[4;5 bcd]-
p y r a n [LXXXVIII, R = H ] . 84-84-5 subl. 97
3:7-dimethoxy-4:6-dihydroxyphenanthrene
(sinomenol) . . . . . . 172 100
Sinomonolquinone . . . . . 259-263 BtOAo needles 103
- - phenazine . . . . . . 272 103
4:0-diacotylsinomenol . . . . 151 112
4:6-diacetylsinomenolquinone 217-219 EtOAo needles 103
-phonazine . . . . . . 256 needles 103
4:6-dibenzoylsinomenol . . . . 206 98
4:6-dibenzoylsinomenolquinone 211 prisms 103
phenazine . . . . . . 254 needles 103
3 : 4 : 6 : 7 - t e t r a m e t h o x y p h e n a n t h r e n e (dimethyl- 123-125 103
sinomenol) 105-6
Dimethylsinomenolquinone . . . . 266 EtOAc prisms 103
phenazine . . . . . . 184 needles 103
Diethylsinomenolquinone . . . . 174 needles 103
phenazine . . . . . . 188 needles 103
4-othylsinomenol . . . . . . 135 110
4-ethyl-6-methylsinomenol . . . . 95 110
4-othyl-6-benzoylsinomenol . . . . 104 110
l-bromo-4-methylsinomenol . . . . 134 CHCl 3 prisms 107-8,
109
l-brorno-4-ethylsinomenol . . . . 137 110
l-bromo-4 iB'-diothylsinomonol 110
l-liromo-<liO-diaooty]Binomenol 187 HOAo prisms 112
l-brorao-017.dimothoxy-8-mothylmorphenol 143 MoOH prisms 107
OH. XXVH DERIVATIVES OF P H E N A N T H R E N E 391
Solvent
for Crystal
Compound m.p. C. recrystn. form Befs.
1:l'-disinomenol . . . . . > 310 113
Tetra-acetyl-1: l'-disinomenol 253 113
Tetrabenzoyl-1: l'-disinomenol 280 needles 113
T e t r a m e t h y l - 1 : l'-disinomenol 240 needles 113
T e t r a e t h y l - 1 : l'-disinomenol . . . . 184 needles 113
4:4'-dimethyl-bis-5:5'-sinomenol 310 HOAc prisms 114
4:4'-dimethyl-6:6'-diaoetyl-bis-5:5'-sinomenol 230 MeOH prisms 114
4 : 4 ' : 6:6'-tetramethyl-bis-5:5'-sinomenol . 283 acetone prisms 114
4:5'-dimethoxy-5:6'-di(benzoyloxy)diphenic
acid . . . . . . . 233-235 rosettes 104
dimethyl ester . . . . . 170-173 MeOH 104
4 : 5 : 5 ' : 6 ' - t e t r a m e t h o x y d i p h e n i c acid 206-208 Et1O prisms 104
dimethyl ester . . . . . 132 MeOH 104
2 : 3 : 3 ' : 4'-tetramethoxydiphenyl 96-100 MeOH plates 104
FROM HASTJBANONINB
Trimethoxyhydroxyphenanthrene . 187-188 MeOH square 117
crystals
TrimethoxyaeetOxyphenanthrene 123-124 MeOH plates 117
Tetramethoxyphenanthrene . . . . 155-167 MeOH prisms 117
131 MeOH prisms 117
B I B L I O G R A P H Y TO C H A P T E R XXVII
1. GtTLiAND and ROBINSON, J.G.S., 1923, 20. PSOHOBE and DICKHATJSER, Ber., 1911,
980. 44, 2633.
2. GRIMATJX, Compt. Rend., 1881, 9 1 , 2 1 . VONGEBIOHTEN, ibid., 1900, 3 3 , 352,
591. 22. ibid., 1898,31, 3198.
3. Ann. CUm. Phys., 1882 (5), 27, 23. ibid., 1899, 32, 1521.
273. 24. ibid., 1898,31, 51.
4. K N O B B , Ber., 1894, 2 7 , 1144. 25. andDiTTMEB,ibid., 1906,39,1718.
5. PSCHOBB, R O T H , a n d TANNHATJSEB, 26. PSCHOBB, Ann., 1912, 391, 40.
ibid., 1906, 39, 19. 27. BtTBGEB a n d AVAKIAN, J.A.C.S.,
6. K N O R B a n d SMILES, ibid., 1902, 35, 1940,62, 226.
3010. 28. EEETTND and S P E Y E B , Ber., 1911, 4 4 ,
7. ibid., 1889,22, 181. 2339.
8. VONGERICHTBN, ibid., 1896, 29, 65. 29. F I S C H E B a n d VONGEBIOHTEN, ibid.,
9. MosBTTict a n d M E I T Z N E B , J.A.G.S., 1886, 19, 792.
1934, 56, 2738. 30. SCHRYVER a n d L E E S , J.O.S., 1900,
10. VONGEBIOHTEN and SCHBOTTBB, Ber., 1024.
1882, 15, 1484. 31. BABGBB, ibid., 1918, 218.
11. SCHBYVEE a n d L E E S , J.G.8., 1901, 32. F I E S E R , J.A.G.S., 1929, 5 1 , 940.
563. 33. Ber., 1931, 6 4 , 701.
12. K N O B B a n d R O T H , Ber., 1911, 44, 34. SMITH, J.G.S., 1916, 568.
2754. 35. VONGEBIOHTEN, Ber., 1899, 32, 1521.
13. a n d HABTMANN, ibid., 1912, 4 5 , 36. ibid., 1898,31, 2924.
1354. 37. SCHMIDT and SOLL, ibid., 1908, 4 1 ,
14. VONGEBIOHTEN, ibid., 1897, 30, 2439. 3696.
15. ibid., 1905,38, 1851. 38. H E S S E , Ann., 1884, 222, 203.
16. SMALL a n d TUBNBULI,, J.A.C.8., 1937, 39. PSOIIOBR, Ber., 1906, 39, 8130.
59, 1541. 40. K N O B B , ibid., 1880, 22, 1118,
17. VONGEBIOHTEN and SOHEOTTHR, Ber., 41. - i b i d . , 1004,37, 3404.
1882, 15, 2179. 42. PBOHOBII and UiUKitXirtinn, Ann.,
18. ibid., 1901,34, 2722. 1010,373,80,
19. K N O B B , BUTLIBB, and HOBMDIN', Ami., 43. -Mid VOQTKIBB, Bw., 1003, 36,
1000,368,300. 4418.
392 DEBIVATIVES OF P H E N A N T H B E N E OH. XXVII
44. VONGBBICHTEN, Ber., 1900, 3 3 , 1824. 82. SCHSPF and H I B S C H , Ann., 1931, 4 8 9 ,
45. PSCHOBB and SUMULEANIT, ibid., 1810. 224.
46. K N O B B and PSCHOBB, ibid., 1905, 3 8 , 83. GOTO and SHISHIDO, Bull. Chem. Soc.
3172. Japan, 1933, 8, 366.
47. a n d W A E N T I G , ibid., 1907, 40, 84. VONGEEIOHTEN and HiJBNBB, Ber.,
3860. 1907, 40, 2827.
48. VONGBBICHTEN, Ann., 1897, 297, 204. 85. PSCHOBB, ibid., 1912, 4 5 , 2212.
49. K N O B B , ibid., 1898, 301, 1. 86. K N O B B and PSOHOBB, ibid., 1905, 3 8 ,
50. Ber., 1889, 22, 2081. 3153.
51. ibid., 1899,32, 742. 87. P S C H O B B and B E T T B E B G , Ann., 1910,
52. ibid., 1905, 38, 3143. 373, 51.
53. H O B L E I N , and STAXJBAOH, ibid., 88. a n d K N O I T L E B , ibid., 1911, 3 8 2 ,
1909,42,3511. 50.
54. SMALL and MALLONEE, J. Org. Chem., 89. K N O B B and H O B L E I N , Ber., 1907, 4 0 ,
1947, 12, 558. 2032.
55. VONGBBICHTEN and W E I L I N G E B , Ber., 90. ibid., 3341.
1905, 38, 1857. 91. PSOHOBB and MASSAOIU, ibid., 1904,
56. J1EBBEESr, Schweiz. Wochschr., 1913, 37, 2780.
51, 1. 92. and LonwEN.^lnm., 1910,373,56.
57. GOTO and KITASATO, Ann., 1930, 4 8 1 , 93. GTJLLAND a n d V I B D B N , J.O.8., 1928,
81. 921.
58. K N O B B a n d S C H N E I D E B , Ber., 1906, 94. PSCHOBB and Z E I D L E B , Ann., 1910,
39, 1414. 373, 75.
59. and H 6 B L E I N , ibid., 1907,40,2042. 95. E B E O T D , Ber., 1894, 27, 2961.
60. ibid., 1906,39, 3257. 96. ibid., 1899, 32, 168.
61. H O L M E S , LEE, and MOOBADIAN, 97. SMALL, J. Org. Chem., 1942, 7, 158.
J.A.C.8., 1947,69, 1998. 98. GOTO, Proe. Imp. Acad. (Tokyo), 1926,
62. MACDONALD and CHEOHAK, ibid., 2,7.
1948,70, 1972. 99. ibid., 2 , 414.
63. HOLMES and L E E , J.A.G.S., 1947, 69, 100. and SHISHIDO, Bull. Chem. Soc.
1996. Japan, 1931,6, 79.
64. PSOHOBB, J A E C K E L , and E E C H T , Ber., 101. J. Agr. Chem. Japan, 1926 (2),
1902, 3 5 , 4377. 2, 17.
65. a n d K A B O , ibid., 1906, 39, 3124. 102. OcHiAi, J. Pharm. Soc. Japan, 1924,
66. EINBEOK, and SPANGENBEBG, 503, 8.
ibid., 1907, 40, 1998. 103. GOTO a n d SuDztno, Bull. Chem. Soc.
67. and BUSOH, ibid., 2001. Japan, 1929, 4 , 163.
68. K N O B B , ibid., 1903, 36, 3074. 104. and SHISHIDO, ibid., 1941, 16,
69. GOTO, SHISHIDO, and TAKVCBO, Ann., 170.
1932, 497, 289. 105. K O N D O and OCHIAI, J. Pharm. Soc.
70. SCHOPF, Pj1EiIfEBB, a n d H I E S C H , ibid., Japan, 1927, 549, 913.
492, 213. 106. Ann., 1929,470, 224.
71. K N O B B , Ber., 1904, 37, 3499. 107. GOTO, ibid., 1931, 489, 86.
72. FBEITND and GOBEL, ibid., 1895,28,941. 108. and A B A I , Bull. Chem. Soc.
73. MICHAELS, and GOBEL, ibid., Japan, 1942, 17, 304.
1897, 30, 1357. 109. and NAGAI, ibid., 1943,18,
74. P S C H O B B and H A A S , ibid., 1906, 39, 143.
16. 110. and NAGAI, ibid., 218.
75. H O W A R D a n d B O S E B , ibid., 1886, 19, 111. A R A I , a n d O D E E A , ibid., 1942,
1596. 17, 393.
76. P S C H O B B , SEYDEL, and S T O H B E B , 112. and SHISHIDO, ibid., 1933,8,366.
ibid., 1902, 35, 4400. 113. and SUDZUKI, ibid., 1929,4,107.
77. B E N T L E Y and ROBINSON, Mxperientia, 114. a n d TAKTTBO, ibid., 1931,6, 126.
1950, 6, 353. 115. Proc. Imp. Acad. (Tokyo), 1926,
78. J.O.S., 1952, 947. 2, 167.
79. VONGEBIOHTBN, Ber., 1902, 3 5 , 4410. 116. A B A I , and ODEBA, Bull. Chem.
80. F B B U N D , ibid., 1905, 38, 3234. Soc. Japan, 1943, 18, 116.
81. B B N T L E Y , BOBINSON, and WAIN, 117. K O N D O , SATOMI, and ODEBA, Ann.,
J.O.S., 1902, 958. Itep. Itsuu Lab., 1051, 2 , 30.
OH. XXVIi DERIVATIVESOFPHENANTHRENE 393
118. GOTLAND and ROBINSON, Mem. Proc. 123. VONGEBICHTEN and SCHROTTEB,
Manchester Lit. Phil. Soc, 1925,69, Ann., 1881, 210, 396.
79. 124. Ber., 1901, 34, 767.
119. K N O S B , Ber., 1904, 37, 3507. 125. ibid., 1162.
120. SCHOPF and BOBKOWSKY, Ann., 126. F B E U N D , ibid., 1910, 4 3 , 2128.
1927, 452, 252. 127. COOK a n d THOMPSON, J.O.S., 1945,
121. VONGEBIOHTEN a n d MiJLLEB, Ber., 395.
1903, 36, 1590. 128. FiNDLAY and SMALL, J.A.G.S., 1950,
122. P S C H O B R and R O L L E T T , Ann., 1910, 72, 3249.
373, 1.
XXVIII
BIOSYNTHESIS AND SYNTHESIS IN
THE MORPHINE-THEBAINE GROUP
I N view of the great chemical and pharmacological interest of the
alkaloids of the morphine-thebaine group, the ultimate verification of
the Gulland-Robinson formulae [1-2] by the synthesis of one of the
alkaloids or of one of their derivatives by an unambiguous route, clearly
showing the attachment of the nitrogen-containing bridge at positions
9 and 13 of the phenanthrene skeleton, has been of major importance.
The first attempts at synthesis were based on the view that the prob-
able mode of biogenesis of these alkaloids is the union of the two
aromatic nuclei of a laudanosine-type of benzyltetrahydroisoquinoline
[3]. This union may be regarded as analogous to the formation of a
terpene from isoprene or of vinylacetylene from acetylene. If the union
occurs in such a position that hydrogen can subsequently be lost with
reformation of an aromatic nucleus, then the product is a base of the
aporphine type, whereas if union takes place in a position already
bearing a substituent, loss of hydrogen cannot occur without migration,
and the resulting base belongs to the morphine group.
MeO MeO
-2 H
AND
NMe NMe
[HI]
Pl
IDENTICAL
BOEMULAB
OH
MeO
AND
KMe NMe NMe
This theory may be illustrated by the base [i], which could hypo-
thotioally undergo union of the two aromatic nuclei in four different
CH. XXVIII THE MORPHINE GROUP 395
ways, two of which would yield aporphine bases, [n] and [in], and the
remaining two would give sinomenine [rv] and an isomer of sinomenine
[v]. Sinomenine, benzyltetrahydroasoquinoline bases of type [i] (e.g.
laudanosine [vi]) and aporphine bases of types [n] (e.g. glaucine [vii])
and [in] (e.g. corytuberine [vni]) are known to occur in nature, but
no morphine-type of alkaloid substituted as in [v] has yet been isolated.
OMe OMe
v '
LXIII] LXIV] [XV]
396 B I O S Y N T H E S I S AND S Y N T H E S I S IN CH. xxvm
Robinson has suggested that a more probable course for the bio-
genesis of thebaine is by way of [xvi] (which could arise from the same
intermediates as [i] with cyclization of the isoquinoline ring oriho
instead of para to the hydroxyl group) and the further intermediates
[xvn] and [XVIII], the latter finally undergoing transposition of the
substituents at C-13 and C-14 to give thebaine [xv], a feasible migration
[3]. I n fact [XVIII] has been considered as a possible formula for the-
baine [3-4], but rejected (see Chap. I).
NMe
M e O ^ / MeO'
[XXV] [XXII] [XXIII] [XXIV]
OEIPAVINE THEBAINB
MeO
NMe
HO 0 ^ ^ ^ HO'
[XXVI] [XXVII] [XXVIII] [XXIX]
NEOPINB MOEPHINONB MOEPHINB CODEINE
HO
2
[XXX] [XXXII]
- O.[XXXIII]
-OH3 -CH 3
O - -- O l
CH3-] /1 CH 3 -J jj
1 ^ ^ O H
V^o
[XXXV] [XXXIV]
NMe
Similarly oxidation of [xxxix] could give [XL] and [XLI], and reduc-
tion of the latter followed by methylation of the enol form of the
product would yield sinomenine [iv] [9].
Waters, who has been thinking on identical lines in Oxford, has
pointed out to the author that an extension of this free-radical mechan-
ism can account for the production of curare alkaloids from those of
tho benzyltetrahydroisoquinoline series.
OH. XXVIII THE MORPHINE GROtTP 399
OH
-COOH C00H /"K/^COOH COOH
CH4-COOH
[XLII] [XLIV]
HO
,NMe2 " CH
COOH CH2J-CH
[XLVI] [XLVII] [XLVIII] [XLIX]
[LU] [LIII]
OJ
[LVII]
COOEt
Cr[LVIII]
COOEt HCl
HEAT COOH
[LIX] [LX]
POCl 3
95%
CH2(J) CH2(I) Cl
k^A^J H2/pt02
E)(J)CH2MgI NaOEt
[LXIV] [LXIII] [LXII] [LXI]
CH2(J)
Br
^fO OONH, Q ^
CH
5 H
Q CH2(J)
(CH2)6N,
y ACID
CH2(J) qii2(J>
CH2(J)
N
NMe
(J)CH 1 COCl I I T POCl
[LXVI] [LXVII] [LXX] [LXXI]
MeO
NMe
OH
MeO-y^H, HOy-V Me0y--%s
HO V ^ k HO-K^K
T l
r^]N^NMe [^PYjIMe NMe
MeOy^X, MeO
O M e O ^ A ^ o Me-
0 ^ > 0
OH 2 -CN
[LXXIX] [LXXXI]
CI
Il
CH2-C-CH = CH2
[LXXXVI]
"^ 1
OH.
HI,
NH NH
CO -co
HEXAHYDRO- DESOXY-
[XCIII] [XCIV]
H2/OuOr03
,OR LiAlH A
NH
2MDTETRAHYDRO-
[LXXX] [XCV] [XC]
^ 3 -NMe
-S-/
[CIV]
(i -DIHYDROTHEBAINONE
l.)3Br2/HOAc/DN-P J 2Br 2
2) ACETONE/ACID HOAc
DNP
MeO MeO'
ACETONE HO
ACID
NMo NMe
HO'
CODEINE l-SROMOCODEINONE l-BROMOTHEBAINONE-A l-BROMOTHEBAINONE-A
DINITROPHENYLHYDRAZONE
[CVIII] [CVII] [CVI] [CV]
NMe
MeO
MeO Me/
Mo
[CXVI] [CXVII] [CXVIII]
O
[CXXIV] [CXXV] [CXXVI] [CXXVII]
CH.; CH CH 5 CH
6 JJEt2
CH2-COOEt
Et 3 N CH3
[CXXXVI] [CXXXVII] [CXXXVIII] [CXXXIX]
^NOa NO2
CH-OOOEt NH NH
CH-ON CH1 CH2
6-C0(J> CH2 CO
0-000
[CXL] [CXLI] [CXLII] [CXLIII]
NH
ICHJ-CCH2-OEt
Et
I CH3COOH '
COOH Ra
MeO Y - " X
HoAJ
CH2I-CH5NH2 CH-CN
COOEt
CH2
CH
rtv
I CIH-CH2NR2
,NR, ,NR2
NMe2 0 ( T \ / ^ - ;NH
HOOC
J CH2CH3 fcH^CHiOEt
Mention must finally be made of the work of Horning and his col-
laborators [57-61], who have synthesized many compounds, such as
[OLIX], [OLX], [OLXI], and [OXLII], t h a t have parts of the morphine
OH. XXVIII T H E M O R P H I N E GROUP 413
B I B L I O G R A P H Y TO CHAPTER XXVIII
1. GtTLLAND a n d ROBINSON, J.G.S., 30. GATES and NEWHALL, Experientia,
1923, 980. 1949, 5, 285.
2. Mem. Proa. Manchester Lit. 31. WOODWABD, NEWHALL, and
Phil. Soc, 1925, 6 9 , 79. KiJNZLi, J.A.O.S., 1950, 72, 114.
3. R O B I N S O N and SUGASAWA, J.O.8., 32. and TSCHUDI, ibid. 4839.
1931, 3163. 33. ibid., 1952,74, 1109.
4. Nature, 1947, 160, 815. 34. R A P O P O B T , L O W E L L , a n d TOLBEBT,
5. a n d SUGASAWA, J.O.S., 1932,789. ibid., 1951, 7 3 , 5900.
6. ibid., 1936, 1079. 35. E I E S E B a n d H O L M E S , ibid., 1936, 58,
7. SCHOPF a n d T I E B F E L D E B , Ann., 1932, 2319.
497, 22. 36. ibid., 1938,60, 2548.
8. R O B I N S O N and SUGASAWA, J.O.S., 37. W I E L A N D a n d K O T A K E , Ann., 1925,
1933, 280. 444, 69.
9. SCHOPF, private communication; 38. F I E S E B and BBADSHEB, J.A.C.8.,
Naturwiss., 5 J u n e 1952. 1939, 6 1 , 417.
10. P U M M E B E B , MELAMED, and PUTT- 39. H O L M E S a n d T B E V O Y , Can. J. Res.,
FABOKKN, Ber., 1922, 55, 3116. 1944, 2 2 B, 56.
11. PUTTFABCKEN, a n d SCHOPF- 40. a n d M A N N , J.A.C.S., 1947, 69,
LOOHEB, ibid., 1925, 58, 1808. 2000.
12. SCHOPF, P E B B E Y , a n d J A O K H , Ann., 41. G H O S H a n d R O B I N S O N , J.C.S., 1944,
1932, 497, 47, 59. 506.
13. B R A S S , JAOOBI, J O B D E , MOCNIK, 42. SARGENT a n d SMALL, J. Org. Chem.,
N E U B O T H , a n d SALZEB, ibid., 1940, 1951, 16, 1031.
544, 30. 43. BABLTBOP a n d SAXTON, J.CS., 1952,
14. A W E , Arch. Pharm., 1934, 272, 466. 1038.
15. E M D E , Ber. Sachs. Akad. Wiss., 1931, 44. ibid., 1947, 399.
83, 219. 45. CBONYN, J. Org. Chem., 1949, 14,
16. G B E W E , Naturwiss., 1946, 3 3 , 333. 1013.
17. Ber., 1939,72, 426. 46. GINSBUBG, ibid., 1950, 15, 1003.
18. ibid. 785. 47. N E W M A N and PABBMAN, J.A.C.S.,
19. ibid. 1314. 1944, 66, 1550.
20. ibid., 1943, 76, 1072. 48. a n d MAGEBLEIN, ibid., 1947, 6 9 ,
21. ibid. 1076. 942.
22. and MONDON, ibid., 1948,81,279. 49. GANGULY, Science and Culhvre, 1941,
23. POHLMANN, a n d SCHNOOB, ibid., 7, 319.
1951, 84, 527. 50. SENGUPTA, GANGULY, a n d B A N E B J E B ,
24. M O N D O N , a n d N O L T E , A n n . , 1949, Science and Culture, 1947,12, 404.
5 6 4 , 161. 51. S O F F E B , CAVAGNOL, a n d GELLBBBON,
25. SCHNTDEB a n d GBUSSNEB, HeIv. Chim* J.A.C.S., 1949, 7 1 , 3857.
Acta, 1949, 3 2 , 821. 52. STEWABT, CAVAGNOL, Q E L L E U -
26. ibid., 1951, 34, 2211. SON, and B O W L E B , ibid., 1050, 7 2 ,
27. a n d H E L L E B B A C H , ibid., 1950,33, 3704.
1437. 53. SARGENT a n d SMALL, Science, 1000,
28. GATES a n d N E W H A L L , J.A.O.S., 1948, 112, 473.
70, 2261. 54. BABLTBOP and NICHOLSON, J.Q.S,,
20. ibid,, 1050, 72, 228. 1051, 2524.
414 SYNTHESIS IN T H E MORPHINE GROUP
55. B I R C H and ROBINSON, ibid., 1943, 60. H O R N I N G , H O R N I N G , and P L A T T , ibid.,
502. 1947, 69, 2929.
56. BAELTBOP and J E F F R E Y S , unpublished 61. ibid., 1948, 70, 2072.
work. 62. KOELSOH, ibid., 1945, 67, 569.
57. H O R N I N G and SCHOCK, J.A.O.3., 1948, 63. i b i d . , 1951, 7 3 , 2951.
70, 2941. 64. STERN, Quarterly Reviews (Chemical
58. ibid. 2945. Society), 1951, 5 , 405.
59. ibid., 1949,71, 1359.
APPENDIX
A D D I T I O N TO C H A P T E R V I
IT was shown in Chapter VI that the degradation of the methohydroxides of
dihydrocodeine methine and a-tetrahydrocodeimethine proceeds with the
production, in addition to the simple nitrogen-free products, of substances
having undergone methylation at the 6OH group. It has since been shown
that the degradation of y-tetrahydrocodeimethine [i] gives also a nitrogen-
free compound in which oyclization has occurred between the 6OH group
and the residue of the C-13 side-chain [I].
The products of dry-distillation of y-tetrahydrocodeimethine methohy-
droxide were separated into the following: 6-y-hydroxy-13-vinyloctahydro-
methylmorphenol [n, R = H ] ; 6-y-methoxy-13-vinyloctahydromethyl-
morphenol [n, R = CH3] and, after removal of olefinic matter by osmium
tetroxide oxidation, 6-codiran [in]. No such cyclic ether could be isolated
from the degradation products obtained from a-tetrahydrocodeimethine
and the formation of such a compound during the degradation of y-tetra-
hydrocodeimethine allegedly shows that in isocodeine the ethanamine chain
at C-14 and the hydroxyl group at C-6 are arranged on the same side of ring
C [I]. Hydrogenation of [II, R = CH3] gave the 13-ethyl compound.
NMe,
A D D I T I O N TO C H A P T E R V I I
TREATMENT of neopine hydrobromide in aqueous formic acid with hydrogen
peroxide affords 1-bromoneopine, whioh can be degraded to l-bromo-/?-
oodeimetbine [2].
5417,1 MO
418 APPENDIX
Solvent for Crystal Specific
Compound m.p. C. recrystn. form rotation Temp. Solvent Befs.
1-bromoneopine . 174 60% EtOH prisms -42-1 18 EtOH 2
acid tartrate . 243d. 96% EtOH prisms 0 18 H,0 2
methiodide 225 65% EtOH prisms 0 18 H1O 2
l-bromo-/3-codeimethine 180 60% EtOH plates +193 18 CHCl, 2
A D D I T I O N TO C H A P T E R I X
DIHYDKODESOXYCODEINE-C dihydromethine [xin] has been prepared by the
sodium and liquid ammonia reduction of a-codeimethine [xiv] [2].
A D D I T I O N TO C H A P T E R X
CODEINOHE and 1-bromocodeinone [xix, R = H] and [xix, R = Br] have
been prepared by the Oppenauer oxidation of codeine [xx, R = H] and 1-
bromocodeine [xx, R = Br] respectively using potassium tf-butoxide and
benzophenone. On reduction with lithium aluminium hydride these two
ketones are converted into codeine [3].
MeO
A D D I T I O N TO C H A P T E R XV
FOLLOWING the epimerization (at C-14) of l-bromo-/?-thebainone-A 2:4-
dinitrophenylhydrazone to 1-bromothebainone-A 2:4-dinitrophenylhydra-
zone [3] (see Chap. XXVIII), it has been shown that in acetic acid or sodium
ethoxide solution /J-thebainone-A is converted into an equilibrium mixture of
j3-thebainone-A and thebainone-A [xxi], the equilibrium favouring the latter
ketone. Utilizing this reaction a method has been developed for the prepara-
tion of thebainone-A in good yield from dihydrothebaine-^ [xxn] [4].
Specific
Compound m.p. 0 C. rotation Temp. Solvent Befs.
198-5-199-5 -74-0 32 CHCl, 3
2:4-dinitrophenyihydrazone 207-208 -1307-0 27 CHCl, 3
/3-dihydrothebainol . . . . . 165-5-166-5 3
methiodide . . . . . . 266-268 3
4-methyl ether . . . . . 152-153 3
4-methyl ether methiodide 243-244 3
<Z-3-dihydrodesoxycodeine-B methyl ether 2 ( 43-5-44
57-5-58 ] +80-0 27 EtOH 3
L( + )-dibenzoyltartrate . . . . 162-5-163 + 44-5 27 CHCl, 3
piorate 230-231 ,, 3
M9-dihydrodesoxycodeine-B methyl ether
D( )-dlbenzoyltartrato . . . . 161-5-162 -44-0 3
dM3-dIhydrodosoxycodoino-B methyl othor
dlbonzoylmoomato 182 .. 3
1-bromooodoinouo 202-S-208-5 -164-0 82 CHCJ, S
8:4-dlnlk'oplipnylhya.mzono . 221-225 -1040-0 87 OHOl, 3
APPENDIX 419
A D D I T I O N TO C H A P T E E X X I
THE 'tetrahydro-thebaine-quinone' reported on p. 291 has been shown to
be in fact dihydro-thebaine-quinone in which the unsaturated ketone system
has suffered saturation. It is also clear from infra-red spectral measurements
that ethyl thebaine-maleate suffers no reduction on hydrogenation, contrary
to the statement on p. 290 [2].
A D D I T I O N TO C H A P T E R X X V I I
ELIMINATION of the side-chain in the morphine series has now been accom-
plished without the production of a fully-aromatic phenanthrene derivative.
The degradation of neopine dihydromethine [xvi] by heating the methiodide
with sodium ct/cfohexyloxide in boiling cyclohexaxiol affords [XVIII] [2] (see
above addition to Chap. VI).
A D D I T I O N TO C H A P T E R X X V I I I
AN oxidation theory of the biogenesis of thebaine was briefly advanced by
Robinson in 1948 and reference was made to the formation of bis-nor-laudano-
sine alkaloids such as oxyacanthine as affording 'some help in regard to the
nuclear oxidations required for the above hypothesis'. Robinson added, 'The
formation of such diphenyl ethers is clearly an oxidative process; it can of
course be imitated in the laboratory in various ways on much simpler
substances' [5]. This discussion of the problem pre-dates the more elaborate
theory outlined by Schop'f.
Eig. 1 shows a synthetic approach to the morphine structure made by
Ginsburg, the correct stereo-chemical arrangement of the rings being ob-
tained. The same synthesis is being carried out in the 3:4-dimethoxy
series, the goal being the synthesis of dihydrothebainone.
STEREO-CHEMISTRY
Rapoport has recently completed the study of the arrangement of groups
at the asymmetric centres in the morphine group. Having already settled
the arrangement at C-5 and C-6 (see the ozonolysis of codeine and isocodeine,
Chapter IV) and at C-6 and C-13 (see above addition to Chapter VI) recent
work has shown the arrangement of the side-chain at C-13 and the hydrogen
atom at C-14 as being cis relative to rings B and C in the normal series and
trans in the /3- (or epi) series, (see Eig. 2).
In the normal series a cyclic imide was obtained as final product, but in
the j8- (or epi) series no such cyclic imide could be obtained.
The arrangement in morphine can thus possibly be represented as follows:
OC-5 and C-6OH; cis in codeine, trans in isocodeine;
C-6OH and C-13side-chain; trans in codeine, cis in isocodeine;
C-13side-chain and C-14H; cis in normal series, trans in ^-series.
I t will be noted that the formulae shown in Eig. 2, used by Rapoport,
intorprot thobenone as a six-momborod other, not as a flvo-momborod other
as olsewhore formulated in this monograph.
4(7.1 IO a S
COOMe
OH-NO 2
WOLFF-KlSHNER DURING
_<
UAIH 4 ATTEMPTED
METHYLATION Q j^g KETALISN. NH
I
NMe
CO-CH. OAo
IDENTICAL WITH
oREVYES N-METHYLMORPHINANE
F I G . 1.
MuO-,
_>. CH;0:
NMe NMe
MoO- N-OH
DIHYDROTHEBAINONE
THEBAINE
MeO I)MeOH/HCl
2.) H 1 O
CO (JH1 3) OH"
CH 1 -ON
NH 1 COOH
F i n . 2.
APPENDIX 421
The five-membered structure, first suggested by Cahn (J.C.S., 1926, 2562),
appeared to be generally accepted at the outset of this work (e.g. Small,
though interpreting thebenone as being a six-membered ether in 1939,
[Small and Browning, J. Org. Chem., 1939, 3, 618] in 1947 was using a
five-membered ether structure for this type of compound, Small, Sargent,
and Bralley, J. Org. Chem., 1947, 12, 847). Accordingly, in the absence of
evidence in favour of either structure the one commonly in use in 1950 was
used throughout this monograph. I t may be of interest to note that thebenol
is generally assumed to have suffered cyclization at the carbon atom in the
^-position relative to the eliminated nitrogen (see Chapter XXV).
It appears now that the six-membered ring structure has been revived and
should it prove correct the thebenone type of formulae in this monograph
will have to be read as six-membered ether structures. The necessity for
this revision however remains to be demonstrated.
B I B L I O G R A P H Y TO A P P E N D I X
1. E A P O P O B T a n d P A Y N E , J.A.O.S., 1952, 3. GATES a n d T S C H U D I , J.A.O.S., 1952,
74, 2630. 74, 1109.
2. B E N T U E Y and THOMAS, Unpublished 4. and H E L G , ibid. 1953, 7 5 , 379.
work. 5. ROBINSOH, Journal of The Royal Society
of Arts, 1948,96, 795.
INDEX
Italics refer to physical properties given in tables. Heavy type refers to the principal
discussion of a, compound.
Acetophenone: replacement of bromine, 141.
2 : 3 ' - dimethoxybenzylidene - 2 : 5 - di- 1-bromo-, 145.
methoxy-, 295; ultra-violet spec- 8-Bromodihydrocodide, 78, 142, 145.
t r a m , 299. 8-Bromodihydromorphide, 142, 145.
2' - hydroxy - 3 ' - methoxybenzylidene- Bromomorphide, 126, 140, 145, 159.
2: 5-dimethoxy-, 295. Buchucamphor, 348.
Allo-^r-codeine, 5, 61, 7 9 f t , 90, 103, 127,
131, 132, 135, 137, 141, 154, 166, 6-Carbamidoaminooodide, 142.
170. a-Chlorocodide, 74, 75, 76, 78, 79, 126,
Molecular compound with isocodeine, 138, 142, 143, 145, 154, 161.
90. derivatives, 133, 146.
N-oxide sulphonic acids, 80, 90. hydrolysis, 131, 132.
l-aceto-8-acetyl-, 80, 90. ozonolysis, 143.
-A, dihydro-, 78, 79, 80, 90, 142, 173. reduction, 127, 128, 129, 149, 156.
-C, dihydro, 79, 90. replacement of chlorine in, 132, 133.
tetrahydro-, 79, 80, 90. 1-bromo-, 134, 145.
6-Aminocodide, 142, 146. 1-chloro-, 145.
8-Aminocodide, 133, 146. 6-methyl-, 72, 134.
Apocodeine, 274, 303, 311. P-Chlorocodide, 74, 75, 78, 79, 126, 129,
ultra-violet spectrum, 275. 135 fl., 142, 145, 149, 161, 243.
Apomorphine, 5, 7, 21, 302 fl., 310. hydrolysis, 137.
colour reactions, 302, 303. ozonolysis, 144.
detection and estimation, 302, 303. reduction, 136, 137, 156.
mechanism of production, 307, 308, replacement of chlorine in, 137, 138.
309. structure, 136.
reactions and degradation, 303. fChlorocodide, 127, 139.
synthesis, 305, 306. alio-, 136, 139.
ultra-violet spectrum, 310. tetrahydro-, 139.
2-amino-, 307, 311. 6-Chlorodihydrocodide, 75, 127, 128, 130,
2-f>-chlorophenylazo-, 307, 311. 134, 142, 145, 155, 345, 362.
6-hydroxy-, 307, 311. 1-ohlorodihydrohydroxy-, 147, 255, 261.
2-nitro-, 307, 311. dihydrohydroxy-, 144,147, 255, 261.
2-nitroso-, 307, 311. 8-Chlorodihydrocodide, 78, 139, 145, 152,
2-phenylazo-, 307, 311. 160.
triacetyl-, 310. 1-chloro-, 145.
tribenzoyl-, 302, 311. jS-Chlorodihydrocodide, 136, 145.
Apomorphine dimethyl ether, 303, 311. 6-Chlorodihydromorphide, 130, 145, 160.
dihydromethine, 304, 311. a-Chloromorphide, 25, 126, 127 ft., 145.
isomethine, 303, 311. hydrolysis, 131.
methine, 303, 311. reduction, 127, 128, 129.
replacement of chlorine in, 132, 133.
Benzene - 1 : 2 : 3 : 4 - tetracarboxylic acid, j3-Chloromorphide, 126, 135 fl., 136, 145,
323, 379. 159.
3 : 4 - Benzocoumarin, 4 ' - acetoxy - 6 : 3 ' - and t h e apomorphine rearrangement,
dimethoxy-, 377. 138, 307, 308.
8:3'-dimethoxy, 377. hydrolysis, 137.
Benzyldihydrothebaine, 284, 288. reduction, 137.
Bisdesmethylsinomenylidene, 348, 364. replacement of chlorine in, 137, 138.
Bisthiooodide, 138, 141, 243, 250. sulpho-, 138, 146.
Bislhiomorphide, 138, 141, 243, 250. a-Ohlorocyanonormorphide, 25, 145, 146.
Bromooodido, 79, 120, 140, 146, 243. a-Codoimathine, 1, 2, G, 6, 7, 9, 63, 100 fl.,
reduction, 141. 101, Ul, 222, 867, 868, 871, 872.
)EX 423
esters, 105. -A, dihydro-, 107, 108, 119.
halogenated derivatives, 105. -B, dihydro-, 107, 108, 119.
Hofmann degradation, 105, 109. -C, dihydro-, 107, 108, 119.
ozonolysis, 115. hexahydro-, 107, 108, 109, 119.
reduction, 106. -A, tetrahydro, 107, 108, 119.
ultra-violet spectrum, 102, 103, 214, -C, tetrahydro-, 107, 108, 109, 119.
224, 276. C-Codeimethine, 80, 103, 118.
acetylbromoiso-, 105, 121. reduction, 109.
acetyldibromodihydro-, 105, 121. -A, dihydro-, 119.
1-aceto-, 114, 120. hexahydro-, 120.
1-bromo-, 110. -A, tetrahydro-, 120.
bromohydroxydihydro-, 105, 106, 121, -C, tetrahydro-, 120.
379. Codeimethylamide:
chloro-, 111, 112, 120, 134, 372. e-bromoamylcyanoacetyl, 116, 121.
cHorodihydro-, 112, 135. co-bromoxylylcyanoacetyl, 116, 122.
chlorotetrahydro-, 118, 135. Codeimethyldihydroisoindole, 116, 121.
cyanonor-, 113, 121. Codeimethylmorpholine, 116, 122.
cyanonoracetyl, 113, 121. Codeimethylpiperidine, 116, 121.
desoxy-, 152, 153, 162. Codeine, 1, 9, 19, 57 f t , 80, 126, 127, 131,
dichloro-, 111, 120, 134. 132, 135, 141, 166, 169, 182, 302,
dihydro-, 106, 118,119; see also Codeine 418.
dihydromethine; Codeine methine, catalytic rearrangement, 66, 219.
dihydro-; Neopine dihydromethine. colour reactions, 58, 59.
dihydrodesoxydihydro-, 112. demethylation, 60.
dihydrodesoxytetrahydro-, 112, 135. detection and estimation, 58, 59.
ethylthio-, 112, 244, 249. esters, 60, 81, 82.
ketodihydro-, 84, 114. ethers, 62, 82.
6-methyl-, 72, 110, 120. Hofmann degradation, 63.
1-nitro, 110, 120. isolation, 57.
1-nitrotetrahydro-, 120. nuclear substitution in, 72.
nortetrahydro-, 114, 121. occurrence, 57.
tetrahydro-, 107, 109, 110, 114,119, 177, oxidation, 64, 65.
416. physical properties, 57.
0-Codeimethine, 2, 5, 6, 9, 11, 63, 101 ft, preparation, 59, 60.
118, 222, 367, 368, 416. reduction, 62.
esters and ethers, 105. salts, 80, 81.
Hofmann degradation, 105, 109. synthesis, 394 ft, 406.
reduction, 106, 107, 416. thermochemical studies, 72.
ultra-violet spectrum, 102, 103, 214, ultra-violet spectrum, 73, 102, 103,
216, 224, 276. 193, 223.
1-aceto-, 114, 120, 374. 1-aceto-, 67, 82.
1-bromo-, 120, 417, 418. 1-amino-, 66, 67, 82.
desoxy-, 152, 153, 162. ' 2-amino-, 67, 82.
ethylthio-, 244, 245. 6-amyldihydro-, 73, 87.
6-methyl-, 72, 110, 120. 7:7'-bishydroxymethyldihydro-, 74,177,
y-Codeimethine, 75, 103, 112, 118, 134, JSO.
368. 1-bromo-, 66, 83.
esters and ethers, 105, 111. 2-bromo-, 82.
reduction, 107. 1-chloro-, 66, 82.
tetrahydro-, 107, 119, 415. dihydro-, 62, 78, 82, 127, 345, 362.
degradation, 415. 7:8-dihydroxydihydro-, 9, 65, 84.
methyl ether, 415, 417. di-iodo-, 66.
3-Codeimethine, 75, 103, 118, 134. 1-ethyldihydro-, 67, 83.
ethylthio-, 112, 248. 6-ethyldihydro-, 73, 87.
-Codeimethine, 9, 63, 78, 103, 118, 134, 1-hydroxy-, 66, 82.
368, 372, 380. 14-hydroxy-, 252, 260.
halogenated compounds, 105. 7-hydroxydihydro-, 6S, 84, 182, 84S,
Hofmann degradation, 104. 362.
reduction, 107. 8-hytlvoxyillhydro-, 182,183.
424 INDEX
14-hydroxydihydro-, 254, 260. structure, 168.
l-(l'-hydroxyethyl)-, 67, 82. trimethoxyphenanthrene from, 168.
l-(l'-hydroxyethyl)dihydro-, 67, 82. amyldihydro-, 266, 270.
6-methyl-, 72, 87, 169. benzyldihydro-, 266, 270.
6-methyldihydro-, 73, 87. 1-bromo-, 170, 179, 418.
methyldihydro-, 264, 270. synthesis of, 406.
isomethyldihydro-, 264, 270. 14-bromo-, 170, 188, 189, 251 ft., 256,
1-nitro-, 66, 82. 261, 268.
2-nitro-, 67, 82. reduction of, 253, 254.
6-phenyldihydro-, 73, 87, 88. 1-bromodihydro-, 345.
Codeine-carbon suboxide, 72, 87. l-bromo-7-methoxy-, 170; see also Sino-
Codeine dihydromethine, 103, 106, 118. meneine, 1-bromo.
ultra-violet spectrum, 103. 14-bromo-l-nitro-, 261.
14-hydroxydihydro-, 257, 260. 14-chloro-, 188, 255, 256, 258, 261.
Codeine methine, 14-hydroxydihydro-, cyanonordihydro-, 178, 179.
257, 260. dihydro-, 7, 168, 172 f t , 179, 199, 204,
Codeine methyl ether, 62, 82. 226, 227, 345.
rearrangement to thebainone-A enol Beckmann transformation of oxime
methyl ether, 62. of, 10, 174, 175, 176, 180.
dihydro-, 82. derivatives of the enol form, 176, 179,
Codeine-narcotine salts, 81. 180.
Codeine-N-oxide, 68, 84. dihydromethine, 107, 177, 180, 206.
dihydro-, 68, 84. enol acetate and reaction with Grig.
Codeine-N-oxide sulphonic acids, 68, 84. nard reagents, 176, 263.
Codeine sulphonic acid, 84. Hofmann degradation of, 177, 178.
dihydro-, 67, 68, 84. Mannich reaction of, 178.
Codeine violet, 72. methine, 106, 177, 180.
0-Codeine, 5, 7, 9, 61, 75 JEE., SS, 103, 126, ozonolysis of, 179.
127, 131, 132, 135, 137, 141, 154, reaction of, with lithium alkyls,
166, 168, 170, 2 4 8 , 2 6 3 . 178.
esters and ethers, 76, SS, 89. reduction of, 176.
Hofmann degradation, 78, 79. dihydrometa-, 174, 181, 240, 242.
replacement of hydroxyl group in, 78. 8:14-dihydroxydihydro, 252, 262.
reduction, 76, 77, 78, 154. ethyldihydro-, 266, 269.
structure, 76. 14-hydroxy-, 9, 170, 188, 189, 225,
l-aceto-8-acetyl-, 79, 89. 251 ft, 259.
1-bromo-, 79, 89. bromination, 258.
l-chloro-, 89. chlorination, 255.
cyanonor- and derivatives, 89. Hofmann degradation of, 256.
-A, dihydro-, 76, 78, 89, 107, 108, 171, methine, 256, 259.
173, 182. preparation of, 251.
-B, dihydro-, 76, 78, 89, 107, 108. reduction of, 252, 253.
-C, dihydro-, 76, 78, 89, 107, 108. structure'of, 252.
1-nitro-, 67, 79, 89. 14-hydroxycyanonor-, 258, 259.
tetrahydro-, 107, 108, 89. 7-hydroxydihydro, 180, 228.
0-Codeine methyl ether, 268. 8-hydroxydihydro-, 182, 183.
-A, dihydro-, 89. 14-hydroxydihydro-, 9, 252, 253, 254,
-C, dihydro-, 89, 132. 256, 259.
methyldihydro-, 268, 271. dihydromethine, 260.
tetrahydro-, 89, 132, 268, 271. dimethyl ketazine, 253.
i^-Codeine-N-oxide, 79, 89. enol acetate, 254, 258, 259.
sulphonic acid, 68, 79, 89. Hofmann degradation, 256, 257.
Codeinone, 1, 2, 64, 131, 166 fi\, 179, 182, ketimine, 253.
187, 418. methine, 256, 260.
addition of water to, 182. oxime sulphonic acid, 258, 260.
rearrangements of, in acid solution, 167. 14-hydroxynor-, 258, 259.
reduction of, 168, 169, 238. methyldihydro-, 264, 265, 269.
stability towards Grignard reagents, womothyldihydro-, 204, 265, 269.
100. wpnitrosodihydro, 174, JISO, 228.
EX 425
N-nitroso-14-hydroxydihydronor-, 258, reaction with Grignard reagents, 207.
260. 1-bromo-, 134, 150, 152, 161.
phenyldihydro-, 266, 270. cyanonor-, 152, 161.
isophenyldihydro-, 266. dihydro-, 62, 76, 79, 129, 130, 150, 151,
isopropyldihydro-, 266, 259. 154, 155, 162, 248.
7:8:14-trihydroxydihydro-, 258, 260. dihydromethine, 135, 162, 416, 418.
i^-Codeinone, 5, 131, 166, 170 ft, 179, 182, methine, 156, 162, 248.
248. ethyldihydro-, 267, 271.
condensation of, with benzaldehyde, ethylthiodihydro-, 151, 162, 247.
171. ct/cZohexyldihydro-, 267, 271.
condensation of, with semicarbazide, 14-hydroxydihydro-, 144, 255, 261.
171. 6-methyldihydro-, 152, 161.
reaction of, with Grignard reagents, methyldihydro-, 267, 270.
172, 284. octahydrophenyldihydro-, 267, 271.
reduction of, 171. phenyldihydro-, 267, 268, 271.
structure of, 171. Desoxycodeine-D, 152, 160, 161, 162.
trimethoxyphenanthrene from, 171. methine, see /J-codeimethine, desoxy-.
dihydro-, 171, 172, ISO. bis-6:6'-dihydro-, 128,141,156,157,163.
derivatives of the enol form, 176. 1-bromo-, 153, 162.
reduction, 171. dihydro-, 128, 141, 151, 153, 156, 162.
methyldihydro-, 172, 180, 284, 288. dihydromethine, 134, 156, 163.
tetrahydro-, 171, 180. methine, 156, 163.
Codeone, dihydrohydroxy-, 256, 260. Desoxycodeine-E, 63, 153, 162.
tetrahydrohydroxy-, 256, 260. methine, see a-codeimethine, desoxy-.
Codinal: cyanonor-, 153, 162.
a-chloro-, 146. dihydro-, 157, 163, 254.
chlorodihydro-, 146. Desoxycodeine:
dihydro-, 26, 71, 87. 1-bromotetrahydro-, 152, 163.
14-hydroxydihydro-, 258, 261. a-dihydro-, 128, 156.
6-ketodihydro-, 179, 180. ci/ciohexyltetrahydro-, 267, 271.
Codiran, 415, 417. 14-hydrox'ytetrahydro-, 253, 261.
Codizal 3-methyl ester methine, 7:8-di- 6-methyltetrahydro-, 152, 164.
hydro-, 115, 121. phenyltetrahydro-, 267, 271.
Codizonal 3-methyl ester methine, 6-keto- tetrahydro-, 29, 79, 128, 129, 136, 137,
7:8-dihydro-, 115, 121. 150, 151, 152, 156, 157, 163, 227,
Codizone: 255, 336, 338, 339, 343.
anhydro-, 142, 146. dihydromethine, 154, 159, 163.
chloro-, 142, 146. methine, 159, 163.
desoxy-, 142, 146. Desoxyepistephanine, 310.
dihydro-, 146. Desoxymorphine-A, 129, 130, 141, 159,
Cucoline, 333. 164.
Desoxymorphine-C, 160, 164.
Desoxycodeine-A, 128, 129, 130, 149, 150, Desoxymorphine-D, 80, 141, 160, 164.
154, 161, 373. bis-6:6'-dihydro-, 161, 164.
methine, 150, 161. dihydro-, 141, 160, 161, 164.
methyl ether methine, 150, 161. Desoxymorphine-E, 159, 164.
1-bromo-, 150. Desoxymorphine:
dihydro-, 154, 162. dichlorodihydro-, 138, 164, 307, 308.
Desoxycodeine-B, 129, 150. tetrahydro-, 159, 160, 161, 164.
dihydro-, 67, 76, 79, 129, 130, 150, 151, Desoxyneopine, see Desoxycodeine-D.
154, 155, 162, 248. Dicodeylmethane, 72, 87.
dihydromethine, 135, 155, 162. 8-Diethylaminocodide, 133, 146.
methine, 162. 8-Diethylaminocyanonormorphide, 25,
methyl ether, 155. Dimethylamine, 104.
/3-Desoxycodeine-B methyl ether, dihydro-, 8-Dimethylaminocodide, 133, 146.
12, 155, 162. j8-Dimethylaminoethanol, 2, 8, 104, 111,
synthesis of, 405. 245, 872, 873, 380.
Deaoxyoodeine-O, 62, 127, 128, 180, 150, i8-Dimethylaminoothyl ethyl other, 3,104,
151, Ul, 172, 247, 840, 802. 168, 872, 874.
426 IN
Dimorphenylmethane, 27, 38. Flavothebaone, 189, 2 9 3 , 300.
Diphenaldehyde, 5:6:5'-trimethoxy, 278, derivatives, 301.
286. structural speculations, 294 H.
Diphenic acid: ultra-violet spectrum, 299.
6-acetoxy-5:5'-dimethoxy-, 377. Flavothebaone trimethyl ether, 293, 300.
4 : 5'-dimethoxy-5 : 6'-di(benzoyloxy)-, Beckmann transformation of oxime,
335, 382. 293.
4:5:5':6'-tetramethoxy-, 335, 383. Dihydro-derivative, 301.
5:6:5'-trimethoxy-, 278, 286, 335, 377. Methine, 301.
Diphenyl, 128. Fluorenone:
2:3:3':4'-tetramethoxy-, 335, 383. 1:6-dihydroxy-4:5-dimethoxy-, 378.
1 : 4 : 5 : 6-tetramethoxy-2-carboxy-, 378. 1:4:5:6-tetramethoxy-, 378.
Disinomenine, 231, 355, 356, 364. 1:5:6-trimethoxy-4-carboxy-, 378.
tetrahydro-, 355, 364.
^-Disinomenine, 231, 355, 356, 364. Halogenocodides, 5, 60, 61, 126 fi.; see a-
tetrahydro-, 355, 364. and j3-chlorocodide, bromocodide,
Dithiocodide: and iodocodide.
dihydro-/3-diethyI, 245, 246, 249. Halogenomorphides, 20, 21, 126 H.; see a-
dihydro-8-diethyl, 247, 250. and /!-chloromorphide, bromomor-
phide, and iodomorphide.
Ethebenine, 326, 331. Hasubanonine, 12, 357, 358, 359, 364.
Ethebenol, 327, 331, 381. colour reactions, 358.
|8-Ethylaminooodide, 22. methine, 358, 364.
Ethylene, 104. structural speculations, 358, 359.
( + )-2-{2-Ethyl-5-methoxyphenyl)-3: 4-di- Heroin, 19, 26, 32.
methoxydibenzyl, 280, 286. 9- (or 10-) Hydroxycodeine, 4, 64, 65, 83,
Ethylmorphine, see Morphine ethyl ether. 114.
methine, 101. degradation of, 64, 65, 114.
Ethylphenyldihydrothebaol, 280, 285. methine, 64, 84, 114, 375.
Ethylphenylhexahydrothebaol, 280, 285. diacetyl-, 84.
cc-Ethylthiocodide, 62, 153, 243, 244, 245, 1-nitro-, 84.
247, 249.
degradation, 244, 245. Iodocodide, 142, 145, 149.
preparation, 243. Iodomorphide, 142, 146.
reduction, 244. Isocodeine, 5, 61, 7 4 , 88, 103, 127, 131,
structure, 244. . 137, 166.
J3-Ethylthiooodide, 62, 219, 220, 243, 2 4 5 , degradation, 75.
249, 293. methyl ether, 75, 88.
degradation, 247. N-oxide, 75, 88.
methine, 244, 245, 247, 249. N-oxide sulphonic acid, 88.
preparation, 243, 245. l-aceto-6-acetyl-, 88.
reduction, 245. dihydro-, 74, 75, 78, 88.
structure, 245, 246. ozonolysis, 75.
sulphone, 247, 249. Isomorphilactonic acid, tetrahydro-, 75,
sulphoxide, 247, 249. 88.
8-methylthiodihydro-, 246, 249. Isomorphilactonic acid methyl ester, tetra-
y-Ethylthiocodide, 243, 2 4 7 . hydro-, 75, 88.
S-Ethylthiocodide, 77, 133, 154, 155, 243, a-Isomorphine, 2 8 , 38, 131, 141.
245, 2 4 7 , 249. ethers, 28, 38.
degradation, 248, 249. dihydro-, 28, 38.
methine, 248, 250. P-Isomorphine, 2 8 , 38, 79, 130, 131, 141.
reduction, 247, 248. ethers, 29, 38, 141.
structure, 247. dihydro-, 29, 38.
-A, dihydro-, 248, 249. tetrahydro-, 28, 38.
-B, dihydro-, 133, 248, 249. y-Isomorphine, 2 9 , 39, 131, 141.
a- (or 8-) Ethylthiomorphide, 250. ethers, 29, 39.
j3-Ethylthiomorphide, 220, 249, 250. dihydro-, 29, 39.
Eugonol, ultra-violot spectrum, 102. tetrahydro-, 29, 39.
/jtoougonol, ultra-violet spectrum, 102. Isomorphitetrol, totrahydro-, 75, 88.
EX 487
Isothobaino, 322, 32f>. 6 - hydroxy - 13 - uldohydofioinhyriro-
colour !'(motions, 322. methyl-, 415, 411.
degradation, 322, 323. 6 - hydroxy - 13 - carboxyflotaliydro-
ullra-violot npoetrum, 323. methyl, 415, 411.
unBuoooHHi'ul attempts ot synthesis, 6-hydroxy-13-cyanooota]iydi,'omothy]-,
324. 415, 417.
Isothoboniuo and dorivativos, 330,332,350. 6 - hydroxy - 13 - (a : /3 - dihydroxyothyl)
octahydromethyl-, 415, 417.
Metacodeino: 6 - hydroxy -13 - ethyloctahydromethyl-,
dihydrodoeoxy-, 239, 242. 109, 120.
tetrahydrodesoxy, 239, 242. 6 - hydroxy -13 - vinylhexahydromethy 1-,
Metacodeinono, dihydro-, 174,181,240,242. 64, 109, 120.
Metathebainol, 239, 242. 6 -hydroxy -13 - vinyloctahydromothyl-,
anhydro-, 239,- 242. 109, 120, 415, 411.
dihydro-, 239, 242. 6-keto-13-ethyloctahydromethyl-, 205,
Metathebainone, 3, 10, 167, 169, 187, 218, 206, 209.
238 fi., 241, 317, 319. 6-keto -13 -vinylhexahydromethyl-, 178,
degradation, 240, 373. 205, 209.
dihydromethine, 240, 241. 6 - methoxy -13 - ethylhexahydromethy 1 -,
methine, 240, 241. 205, 209.
reduction, 238, 239. 6 -methoxy -13 -vinylhexahydromethyl-,
ultra-violet spectrum, 275, 299, 318. 205, 209.
dihydro-, 238, 239, 241. 6 - methoxy -13 - vinylootahydromethyl-,
dihydromethine, 240, 241. 109, 120, 415, 411.
methine, 240, 241. 6 -methoxy -13 - vinyltetrahydromethyl-,
i/r-Metathebainone, 240, 242. 205, 209.
1: l'-di-Metathebainone, 240, 242, 374. 6-methyl-6-hydroxy-13-ethyloctahydro-
tetrahydro-, 240, 242. methyl-, 110, 120.
Methebenine, 219, 326, 331. 6 - methyl - 6 - hydroxy - 13 - vinylhexa-
Methebenol, 326, 331, 381. hydromethyl-, 110, 120.
9:10-dihydro-, 331. 6-methyl-3-methyl-, 110, 370.
4-Methoxyphthalic acid, 278, 284, 378. Morphidine, 26.
6-Methoxymethylthebentriene, 283, 288. Morphilactonic acid and its methyl ester,
6-Methoxythebendiene, 217, 218. tetrahydro-, 70, 87.
6-Methoxythebentriene, 216, 217, 218,230. Morphimethine, $-, 116, 121.
Methyldihydro-ii-codeine methyl ether, 6-acetyldihydro-, 115, 121.
79, 268, 211. 6-acetyltetrahydro-, 115, 121.
Methyldihydro-i/r-codeinone, 172, 180, 284, tetrahydro-, 116, 121.
288. Morphine, 1, 2, 6, 7, 9, 15 ft., 30, 303.
Methyldihydrothebaine, 282 ft., 287. colour reactions of, 17, 18.
degradation, 282 ft. detection and estimation, 17, 18.
methine, 282, 283, 287. esters, 19, 20, 32, 33.
isomethine, 282, 287. ethers, 19, 33, 3d, 35.
dihydrohydroxy-, isomethine, 283, 288. extraction of, 16.
Methyl - 9 - dimethylamino - 6 - methoxy the- heteroethers, 20, 33, 34.
bentriene, 283, 288. occurrence, 15.
Methyl-^-epistephanine, 317. ozonolysis of, 26.
Methylmorphimethines, see Codeimethines. oxidation of, 22.
Morphenol, 78, 367 ft, 388. physical properties of, 16, 30.
6-y-acetoxy-13-cyanooctahydromethyl-, polymers of, 21.
415, 417. rearrangements of, 21, 22.
l-acetyl-3-methyl, 67. reduction of, 22.
4-acetyl-3-methyl, 78, 388. synthesis of,
jS-bromo-, 370. thermochemical studioe of, 27.
l-bromomethyl-, 368, 370. titration of, 16.
0-bromomethyl-, 370. ultra-violet spootrum of, 78, 807,
l-bromo-3-mothyl-6:7-dimothoxy-, 340. 1-nootyl-, 23, 36.
8-othylthio -18 vinylfcotrabydromothyl-, 8-iwotyl-, 19, 32.
2*0, UO. 6-aootyl-, 10, 3%.
428 INDEX
2-amino-, 24, 36. 6-keto-13-ethyloctahydromethyl-, 205,
1-bromo-, 23, 36. 209.
2-bromo-, 24, 36. methyl-, 104, 372.
diacetyl-, see Heroin. quinone, 371.
dihydro-, 22, 26, 35, 130, 345, 362. bis-3-methyl-4-acetyl-, 240, 374.
N-oxide sulphonic acid, 37. 3-methyl-4-benzoyl-, 372.
2-hydroxy-, 36. quinone, 372.
7:7-bis-(hydroxymethyl)dihydro-, 28, 3 - methyl - 4 - (|8 - dimethylaminoethyl)-,
38. 373.
5- (or 7-) methyldihjfdro-, 27, 264, 270. Morpholine, 2, 373.
6-methyldihydro-, 27, 38, 178. Morphorane, 231, 236.
1-nitro-, 24. |3-Morphorane, 231, 236.
1-nitrodiacetyl-, 24, 36. Morphothebaine, 6, 167, 187, 202, 307,
2-nitro-, 24, 36. 314 ff., 320.
nitroso-, 24, 25. colour reactions, 314.
2-phenylazo- and derivatives, 36. degradation of, 314, 315.
a- and (3-tetrabromo-, 23, 36. dimethyl ether methine, 315, 320.
Morphine dimethyl ether, see Codeine mechanism of production of, 317, 318,
methyl ether. 319, 320.
Morphine glycosides, 20, 35. synthesis of dimethyl ether, 316.
Morphine-y-isomorphine, 29, 54, 55, 56. ultra-violot spectrum of, 318.
Morphine-narcotine salts, 27, 3Jf. N-benzoyI, 314, 320.
Morphine-N-oxide, 25, 37. quinone, 314, 320.
sulphonic acids, 25, 37. tribenzoyl-, 314, 320.
Morphine quinnitrol, 24, 38. quinone, 314, 320.
Morphine sulphonic acid, 24, 37.
Morphinic acid, 38. Naphthalanmorpholine, N-methyl-, 373.
a-chloro-, 146. 1:4-Naphthoquinone, 8-carboxy-7-((8-car-
5-desoxydihydro-, 70. boxyvinyl)-2-methoxy-, 379.
dihydro-, 26, 70, 87. Neomorphine, 28, 125.
tetrahydro-, 87. Neopine, 28, 124, 125.
Morphinone: methine, see /3-codeimethine.
amyldihydro-, 266, 270. reduction of, 124.
bonzyldihydro-, 266, 270. 1-bromo-, 417, 418.
dihydro-, 22, 173, 180. Neopine dihydromethine, 103, 106, 109,
reaction with lithium alkyls, 178. 416, 419.
dihydroiso-, 179, 180. degradation of, 109, 416.
ethyldihydro-, 266, 270. ultra-violet spectrum of, 102.
mothyldihydro-, 266, 270. Nitrocodeinic acid, 67, 86.
phonyldihydro-, 266, 270. Norcodeine, 69, 84.
Mopropyldihydro-, 266, 270. acetylcyano-, 69, 84.
Morphinone A 6 -enol methyl ether, di- amino-, 69, 86.
hydro-, 266, 267, 270. cyano-, 84, 85.
Morphitotrol, tetrahydro-, 71, 87. dihydro-, 69, 86.
Morphol, 371,3SS. nitro-, 69, 86.
9:10-quinone, 371. N-alkyl substituted, 85.
synthesis of, 372. N-aryl substituted, 85.
l-acetyl-3-methyl-, 67, 114, 374. N-nitroso-, 69, 85.
4-acetyl-3-methyl-, 4,104, 111, 372, 388. N-nitrosodihydro-, 69, 70, 86.
quinone, 372, 375. Norcodeinium-dihydroisoindolinium io-
synthesis of, 372. dide, 116.
l-bromo-3-methyl-4-acetyl-, 373. Norcodeinium-morpholinium iodide, 116.
diacetyl-, 370, 371, 388. Norcodeinium-piperidinium iodide, 116.
quinone, 371, 388. Norcodylhydrazine, 70, 85, 86.
bis-diacotyl, 53, 374, 389. Normorphine and its derivatives, 25,26,37.
1 diaootylamino-4-aoetyl-3-methyl-, 374. cyano-, 25, 37.
dlmothyl., 2, 8, 872, 878, 388. diaootyloyanodihydro-, 26, 37.
synthosia of, 878. dihydro-, 20, 37.
bin-dimethyl, 84, 874, 389, Nltvonoroodolnia ooid, 86.
IN EX 429
Norphenyldihydrothebaine, 273, 281, 286. 3:4-dimethoxy-8-vinyl-, 304, 311, 375.
Northebenine, cyano-, 328, 332. 3-methoxy-4-acetoxy-, 4, 104, 111, 372;
Northebenol, 327, 331. see also Morphol, 4-acetyl-3-methyl-.
3-methoxy-4:6-diacetoxy-, 5, 64, 105,
O-desmetbyldihydrothebainone, 220, 234. 167, 330, 350, 376, 380.
O-desmethylthebainone-A, 22, 220, 233, 3-methoxy-4:8-diacetoxy-, 5, 170, 380.
249. 3-methoxy-4:9- (or 10-) diacetoxy-, 4,
Oripavine, 19, 192, 193, 194, 330. 64, 111, 114, 134, 374.
Oxyethebenol, 327, 328, 332. 3-methoxy-4:6-dihydroxy-, 168, 376.
Oxymethebenol, 328, 332. 3-methoxy-4-hydroxy-, 104, 372; see
a-Ozodihydrocodeine, 26, 70, 71, 86. also Morphol, methyl-.
acetyl-, 86. 3 - methoxy - 4 - hydroxy - 1 3 - ethylocta-
6-chloro-, 86, 87. hydro-, A 6 -enol methyl ether, 205,
jS-Ozodihydrocodeine, 71, 86. 209.
y-Ozodihydrocodeine, 71, 86. 2-methyl-, 267.
a-Ozodihydroethylmorphine, 26, 70, 86. 4-methyl-, 267.
j8-Ozodihydroethylmorphine, 71, 86. 3:4:6:8-tetramethoxy-, 315, 321.
y-Ozodihydroethylmorphine, 71, 86. synthesis of, 380.
Ozodihydroisocodeine, 75, 88. a;-tetramethoxy-, 358, 364.
3:4:6:7-tetramethoxy-, see Sinomenol,
Pentachlorooxycodide, 144, 147. Dimethyl-,
Phenanthrene, 2, 26, 104, 284, 333, 334. tetramethoxyvinyldihydro-, 341, 342,
l-acetyl-3-methoxy-4-hydroxy-, 67,114. 384.
l-bromo-3-methoxy-4-acetoxy-, 105. 3:4:6-triacetoxy-, 220, 350, 379.
l-bromo-3-methoxy-4:6-diacetoxy-, 228. 3:4:5-trihydroxy-, 369.
l-bromo-3:4:6-triacetoxy-, 379. 3:4:5-trimethoxy-, 3, 369.
3:4-diaoetoxy-, 370, 3 7 1 ; see also Mor- synthesis of, 369.
phol, diacetyl-. 3:4:6-trimethoxy-, 2, 5, 131, 167, 186,
3:4-dihydroxy-, 370, 371; see also Mor- 376, 378.
phol. synthesis of, 378.
synthesis of, 371. 3:4:8-trimethoxy-, 5, 28, 76, 131, 304,
3:4-dimethoxy-, 2, 3 ; see also Morphol, 311, 327, 375, 380.
dimethyl-. synthesis of, 380.
3:6-dimethoxy-4-acetoxy-, 3, 106, 186, x-trimethoxy-, 323, 325.
375; see also Thebaol, acetyl-. a:-trimethoxyacetoxy-, 358, 364.
3:4- dimethoxy - 6 - amino -13 - ethylocta- 3:4:8-trimethoxy-5-aldehydo-, 328,332.
hydro-, 207, 209. 3:4:6-trimethoxy-8-amino-, 315, 321.
3:7-dimethoxy-4:6-dihydroxy-; see Si- 3:4:8-trimethoxy-5-ethyl-, 327,332,380.
nomenol. 3:4:6-trimethoxy-8-vinyl-, 315,320,380.
3:4-dimethoxy-5:6- (or 6:7-) dihydroxy- 3:4:8-trimethoxy-5-vinyl-, 327,331,380.
13-ethyloctahydro-, 207, 210. x-trimethoxy-8-vinyl-, 322, 325.
3 : 4-dimethoxy-8-(a/3-dihydroxyethyl)-, trimethoxyvinylketotetrahydro-, 341,
304, 311. 384.
3 : 4 - dimethoxy - 6 - dimethylamino -13- Phenanthrene-5-carboxyIic acid:
ethyloctahydro-, 207, 209. 3:4-dimethoxy-8-ethoxy-, 328, 332.
3:4-dimethoxy-8-ethoxy, 327, 328, 332, 3:8-dimethoxy-4-hydroxy-, 328, 332.
380. 3:4:8-trimethoxy-, 316, 327, 328, 331,
3:4-dimethoxy-8-ethoxy-5-vinyl-, 328, 332, 380.
331, 380. Phenanthrene-8-carboxyIio noid:
3 : 4 - dimethoxy - 1 3 - ethylhexahydro-, 3:4-dimethoxy-, 304, 311.
207, 209. 3:4:6-trimethoxy-, 818, 320.
3:4-dimethoxy-13-ethylootahydro-, 207, Phenanthrene - 1 : 4 - quinono, 81fl- dimeth-
209. oxy-, 878, 870.
3:6-dimethoxy-4-hydroxy-, 2, 376; see Phenanthrylono oxiiloi
also Thebaol. 3:6-dihydroxy-, 8,
3 : 6 - dimethoxy 4 - hydroxy - 1 8 - othyl- O-hydroxy-S-methoxyhaxiiliydfO., 410,
totraliydro-, 217, 218. 411.
8 i 4 dimethoxy 0 katoplienyHietaft- 8-methoxy.8-mithyl, 7i,
hydro-, SOO, IiOO. I'honnssitia, T'-mqthoxyimplibha. 1' i ', 871.
430 INDEX
Phenyldihydrothebaine, 6, 11, 202, 272 fi., Sinomelone, 354.
284, 285. anhydrobis-, 354, 364.
dihydromethine, 278, 285. anhydrobisdihydro-, 354, 364.
dihydroisomethine, 279, 285. Sinomeneine:
halogenation, 281, 282. 1-bromo-, 335, 344 fi., 361.
Hofmann degradation, 278 fi. degradation of, 346.
methine, 274, 278, 280, 285. dihydromethine, 346, 361.
isomethine, 278, 279, 280, 285. methine, 346, 361, 384.
oxidation, 278. 1-bromodesmethoxydihydro-, 345, 347,
reduction, 280. 361.
structure and mechanism of forma- methine, 347.
tion, 277. desmethoxydesoxysinomeneine ( ( + )-
ultra-violet spectrum, 275. dihydrocodeinone), 347, 361.
ultra-violet spectrum of methine, 276. dihydromethine, 347, 362.
hexahydro-, dihydroisomethine, 279, methine, 347, 361.
285. Sinomeneine ketone, 1-bromo-, 232, 249,
Phenyldihydrothebainic acid, 282, 287. 350.
Phenyl - 9 - dimethylamino - 6 - methoxy the- Sinomeneinic acid, 1-bromo-, 232, 353,
bendiene, 279, 285. 363.
Phenyl-6-methoxythebenane, 279, 285. Sinomenilan, dihydro-, 355, 364.
Phenyl-6-methoxythebentriene, 279, 285. dihydromethine, 355, 364.
Phenyltetrahydrothebaimine, 272, 280, methine, 355, 364.
281, 286. Sinomenilic acid, 3 5 3 , 363.
hexahydro-, 281, 286. 1-bromo-, 353, 363.
Phenyltetrahydrothebaine, 281, 281. l:7-dibromo-, 353, 363.
6-Piperidocodide, 142, 146. Sinomenilone, 354, 355, 364.
8-Piperidocodide, 133, 147. 1-bromo-, 232, 354, 364.
6-Piperidomorphide, 142, 146. 6:6'-dichlorodihydro-, 355, 364.
Porphyroxine, 98 fi., 100. dihydro-, 354, 364.
colour reactions, 98. dihydromethine, 354, 364.
acetyl-, 98, 100. methine, 354, 364.
methyl-, 98, 100. methyldihydro-, 353.
methyltetrahydro-, 98, 100. Sinomenine, 12, 225, 231, 232, 333 ft, 359.
Prothebenine, 326, 331. bromination of, 335.
J'rothebenol, 327, 331, 381. degradation of, 340 fi.
Protocateehnic acid, 26. reaction with cyanogen bromide, 340.
Protosinomenine, 356, 357. reaction with diazonium salts, 339.
synthesis of, 357. reaction with formaldehyde, 339.
PsoudomorpMne, 22, 51 ff., 55. reduction of, 335 fi.
degradation, 53, 374. ultra-violet spectrum of, 356.
detection, 53. 1-aminodihydro-, 339, 360.
estimation, 53. 1-benzeneazo-, 339, 360.
preparation, 51. 1-bromo-, 335, 359.
tetrahydro-, 54, 55. reduction, 339.
totrahydrodidesoxy-, 55, 56. 1-bromoiso-, 344.
a-Pseudomorphine, 54, 55. cyanonorbenzoyl-, 340, 360.
j3-Pseudomorphine, 54, 55. cyanonormethyl-, 340, 360.
y-Pseudomorphine, 54, 55. desmethoxy-, 349.
octahydro-, 55, 56. desmethoxydesoxydihydro-, 336, 337,
tetrahydro-, 54, 55, 56. 338, 339, 361.
Pyran,3-methoxy-5-methyl-5-phenanthro- dihydromethine, 343, 361.
[4:5-00(2]-, 381. methine, 343, 361.
Pyreno, 192, 329, 381. desmethoxydihydro-, 336, 337, 339, 360.
Pyridino, 26. dihydromethine, 229, 343, 361.
Pyrrolino, 20. methine, 229, 343, 361.
bis-lil'-desmethoxydihydro-, 231, 343,
Quinolino, 20.
361.
Sfnonwton, 88fl, SM. dihydromothine, 848, SOl,
dihydro.,flflfl,804. moUiine, 843, 301.
IEX 431
bis-8:8'-desmethoxydihydro-, 336, 339, Sinomenol quinone, 334, 382.
360. diacetyl-, 334, 382.
desoxytetrahydro-, 336, 338. dibenzoyl-, 334, 335, 382.
diacetyl-1-bromodehydro-, 351, 363. oxidation of, 335, 382.
dihydro-, 335, 339, 349, 360. diethyl-, 382.
dihydromethine, 342, 360. dimethyl-, 341, 382.
methine, 342, 360. Sinomenylidene, bisdesmethoxy-, 348, 364.
1:5-di(hydroxymethyl)-, 340, 360. Stilbene, (-f)-3:4-dimethoxy-2-(5-meth-
dimethyl-1-bromodehydro-, 351, 363. oxy-2-vinylphenyl)-, 278, 286.
5-hydroxymethyl-, 340, 360. Sulphomorphide, 21.
5-hydroxytnethyldihydro-, 340, 360.
N-methylanhydro-, 340. Tetramethylethylenediamine, 104, 111,
Sinomenine hydrate, 339, 347, 348, 352, 372, 373.
362. Thebacodine:
desmethoxy-, 349. dihydro-, 226, 227, 338.
Sinomenine methine, 1-bromodehydro- dihydrohydroxy-, 253.
meta-, 346, 361, 384. Thebaicine, 330, 332.
Sinomenine ac/womethine, 340, 341, 360. Thebainan, dihydro-, 339.
Sinomenine rajeomethine, 340, 341, 360. Thebaine, 1, 2, 8, 9, 12, 166, 167, 184 ff.,
Sinomenine moZeomethine, 340, 341, 360. 193, 272, 314, 326, 376.
Sinomenine 1-sulphonic acid, 349. colour reactions of, 185.
Sinomeninic acid, 352 H., 363. composition of, 186.
1-bromo-, 232, 352, 363. degradation of, 186, 376.
methyl-, 353, 363. Diels-Alder reactions of, 189, 289 fi.
Sinomeninol, 336, 338, 361. estimation of, 186.
desmethoxydihydro-, 226, 336, 337, 338, hydrolysis of, 187.
361. isolation of, 184.
dihydro-, 337, 338, 361. occurrence of, 184.
Sinomeninone, 347 fi. ozonolysis of, 189 ff.
acetolysis of, 350. physical properties of, 185, 250 ff.
bromination of, 349. reaction with bromine, 188, 250 fi.
degradation of, 351. reaction with hydrogen peroxide, 188.
reduction of, 349. reaction with Grignard reagents,
1-bromo-, 228, 232, 264, 330, 348, 353, 272 ff.
362. reaction with nitrosyl chloride, 191,
1-bromotetrahydro, 350, 363. 192.
dihydro-, 349, 363. rearrangements of, 187, 188, 238, 314,
dihydromethyl-, 350, 363. 326.
methyl-, 348, 350, 362. reduction of, 197 fi., 226, 238.
tetrahydro-, 350, 363. ultra-violet spectrum of, 193, 214,
Sinomeninone dioxime, 230, 351, 362. 251, 318.
degradation of, 351. 8 (?) - acetyl - 8:14 - dihydroxydihydro-,
Sinomeninone furazan, 351, 362. 251, 262.
dihydromethine, 351, 362. cyanonordihydro-, 204, 209.
methine, 351, 362. dihydro-, 78, 173, 198, 200, 201, 2 0 4 fi.,
Sinomenol, 333, 382. 225.
1-bromodiacetyl-, 345, 346, 384. degradation of, 205 fi.
1-bromodimethyl-, 383. demethylation of, 266, 267.
l-bromo-4-methyl-, 342. dihydromethine, 205, 200, 415.
l : l ' - d i - , 333, 355, 384. methine, 205, 206, 209.
diaoetyl-, 334, 382. reaction with Grignard roaganta, 263 ft*.
4:6-diaeetyl-5-acetoxymethyl-, 340. j3-dihydro-, 166, 107, 108, 200, 201,
dibenzoyl-, 333, 334, 382. 211 fl., 212, 218, 208.
dimethyl-, 333. hydrolysis of, 218, 220.
synthosis of, 334, 883. methijio, 214, 215, IiIS, 222.
4i4'.dimolhylbii.fii5'., 841, 884. mothino, ultra-violet irpeotoum of, 81Oi
4,-obhyl-O-benasoyl-, 884, mothino methyl ether, 813, M, 889.
4-ethyl-0-methyl-, 884. reduotlon el, 218.
tetrumothylbk-OiO'-, 842, 884. tkuhydromotihltio, 813, IiU,
432 IN:
Thebaine [aontd.): Thebainone:
-<j>, dihydro-, 197, 198, 201, 205, 206, 7-aminodihydro-, 228, 234.
211 ft., 217, 218, 292, 418. amyldihydro-, 266, 269.
degradation of, 215 ft 1-benzeneazo-, 233.
dihydromethine, 203, 206, 217, 218, benzyldihydro-, 266, 269.
223, 229. 14-bromo-, 197.
hydrolysis of, 213, 219, 220, 221, 224. l-bromo-7-ketodihydro-, 264.
reduction of, 212, 225. dihydro-, 169, 173, 174, 199, 200, 204,
ultra-violet spectrum of, 214, 223, 212, 219, 220, 221, 255 fi., 234, 336,
275. 348.
nordihydro-, 204. bromination of, 227.
phenolic dihydro-, see -<j>, dihydro-. degradation of, 229 ff.
phenyldihydro-, see Phenyldihydrothe- dihydromethine, 177, 206, 229, 235.
baine. methine, 177, 229, 234.
tetrahydro-, 198,199, 200, 201, 208, 209, reduction of, 226.
210. j3-dihydro-, 221, 226, 234.
dihydromethine, 208. dihydromethine, 222, 223, 229, 234,
Thebaine-acrolein, 290, 300. 257.
Thebaine-hydroquinone, 291,292,293,300. methine, 229, 234.
ultra-violet spectrum of, 298. epidihydro-, oxime of, 202.
O: O-desmethyldihydro-, 300. bis-1: l'-dihydro-, 231, 234.
dihydro-, 292, 300. dihydromethine, 231, 235.
Thebaine-maleic anhydride, 289, 300. methine, 231, 235.
Thebaine-quinone, 291, 292, 300. bis-8:8'-dihydro-, 232, 234, 336.
ultra-violet spectrum of, 298. dimethyldihydro-, 265, 269.
dihydro-, 300, 418. ethyldihydro-, 266, 268.
tetrahydro-, 291, 300, 418. isoethyldihydro-, 266, 268.
Thebainol-A, dihydro-, 226, 231, 236, 244. ethylthiodihydro-, 220, 245, 249.
degradation, 231. ethylthio-O-desmethyldihydro-, 250.
Thebainol-B, dihydro-, 169, 226, 236, 336. 14-hydroxy-, 225, 253, 256, 261.
|3-Thebainol-B, dihydro-, 226, 236, 336. 7-hydroxydihydro-, 228, 234.
synthesis of, 406. 14-hydroxydihydro-, 253, 261.
Thebainol, 14-hydroxy-, 253, 261. dihydromethine, 256, 257, 261.
Thobainol, 7-hydroxydihydro-, 228, 236, methine, 223, 256, 261.
350. 7-methoxy-, see Sinomenine.
Thobainol 6-metliyl ether, dihydro, 198, methyldihydro-, 263, 264, 265, 266, 268.
199, 200, 201, 212. methine, 266, 268.
Thobainone-A, 10, 169, 173, 188, 202, 212, Momethyldihydro-, 263, 264, 265, 266,
213, 2 1 9 , 220, 233, 238, 245, 379, 268.
418. methine, 266, 268.
reduction of, 219. isomethyl-7-ketodihydro-, 264, 268.
ultra-violet spectrum of, 223, 356. methylthiodihydro-, 246, 249.
O-desmethyl-, 22, 220, 233, 249. O-desmethyldihydro-, 220, 234.
b i s - l : l ' - , 231,233. phenyldihydro-, 266, 269.
j3-Thebainone-A, 166, 198, 211, 213, 220, wophenyldihydro-, 266, 269.
221, 233, 418. wopropyldihydro-, 266, 269.
epimerization of, 418. Thebainone-A enol methyl ether, 62, 197,
reduction of, 221. 198, 200, 201, 212, 218, 219, 233,
ultra-violet spectrum of, 223. 245, 292.
Thebainone-B, 213, 214, 2 2 1 , 225, 229, hydrolysis of, 213, 219, 226.
233. reduction of, 198, 212, 226.
dihydromethine, 256, 257, 261. Thebainone A 5 -enol methyl ether, di-
methino, 213, 233, 257. hydro-, 198, 204, 212, 225, 234.
reduction of, 221. dihydromethine, 217, 229, 235.
ultra-violet spootrum of, 223. Thebainone A-enol methyl ether, di-
ultra-violot spootrum of methine, 215, hydro-, 198,199, 200, 201, 212, 226,
224,. 234.
Thobateone-O, 218, 221, 224, 283. a-Thebaizons, 189,104.
ultra-vlolat) npootrum of, 22B, 224, l-bromo", 100, 104.
)EX 433
jS-Thebaizone-, 191, 194. cyanonor-, 188, 332.
Thebaizone: dihydro-, 328, 331.
desoxy-, 190, 194. ,KT-methyl-, degradation of, 327.
dihydro-, 190, 194. Thebenol, 326, 331, 381, 421.
dihydrodesoxy-, 190, 191, 194. Thebenone, 8, 11, 229, 230, 235, 343, 362,
isodihydro-, 191, 194, 208. 419, 420, 421.
a-Thebaizonic acid, 190, 194. b i s - l : l ' - , 231, 235, 343, 362.
methine, 191, 194. bis-l:l'-9:10-dehydro-, 231, 235, 343,
dihydrodesoxy-, 190, 194. 362.
methine, 191, 194. 1-bromo-, 230, 235.
hydroxydihydro-, 190, 191, 194. 8:14-dehydro-, 230.
/3-Thebaizonio acid, 191, 194. 9:10-dehydro-, 229, 235, 343, 362.
Thebaol, 186, 389. 14-hydroxy-, 257.
oxidation of, 378. 7-methoxy-, 342, 362.
acetyl-, 186, 376, 389. 7-methoxy-9:10-dehydro-, 342, 362.
quinone, 377, 389. methyl-9:10-dehydro-, 232, 266, 268.
benzoyl-, 186, 377, 389. womethyl-9:10-dehydro-, 232, 266, 268.
quinone, 377, 389. tetradehydro-, 217, 230, 235.
Thebaone: j8-Thebenone, 229, 231, 236.
methyldihydrohydroxy-, 257, 261. Thebenone ketone, 230, 236, 343, 362.
methyltetrahydrohydroxy-, 257, 261. Thebenone ketone furazan, 231, 351, 352,
tetrahydrohydroxy-, 257, 261. 363.
Thebenane, 231, 236, 343, 363. 9:10-dehydro-, 231, 351, 352, 363.
5:6- (or 6:7-) dehydro-, 113, 231, 236. Thebenylphenylthiourea, 328, 331.
9:10-dehydro- and derivatives, 231, 236, Trichlorocodide, 145.
343, 363. Trichloromorphide, 145.
Thebenidine, 329, 332.
synthesis of, 329. Vinyldihydromethylthebaol, 282, 283, 288.
3:8-dimethoxy-, 329, 332. Vinyldimethylamine, 3, 104.
Thebenine, 5, 7, 167, 187, 326 ff., 331. Vinylhexahydrophenyltetrahydrothebaol,
ethers of, 328, 331. 286.
mechanism of production of, 329, 330. Vinylphenyldihydrothebaol, 285.
reduction of, 328. I Vinylphenyltetrahydrothebaol, 281, 286.