Journal of Chromatographic Science, Vol. 32, December 1994
Cd
Methcathinone and Designer Analogues: Synthesis,
Stereochemical Analysis, and Analytical Properties
Jack DeRuiter, Lisa Hayes, Allen Valaer*, and C. Randall Clarkt
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Auburn, Alabama 36849
FIT. Nogele
‘Alabama Department of Forensic Sciences, Wire Road, Auburn, Alabama 36831
This paper describes the synthesis, stereochemical analysis, and
analytical properties of methcathinone and related compounds.
Methcathinone represents a new class of designer street drugs that
can be prepared easily from readily available starting materials,
such as the ephedrines and pseudoephedrines. The oxidation of
each individual isomer of ephedrine and pseudoephedrine
produces homochiral methcathinone via conservation of
configuration. Thus 1R,2S-ephedrine and 15,25-pseudoephedrine
yield $smethcathinone, and 15,2R-ephedrine and 1R,2R-
pseudoephedrine produce R-methcathinone. The isomers of
methcathinone were separated by gas chromatography as the
diastereomeric amides following derivatization with S-(-)-N-
(triluoroacetyNprolyl chloride (TPC).
The gas chromatographic-mass spectrometric analysis of
methcathinone and designer analogues showed a major
chromatographic peak with a mass spectrum characteristic of the
parent molecule. However, the major chromatographic peak was
accompanied by a secondary, well-esolved peak that yielded a
molecular ion 2 mass units less than that ofthe major peak.
Deuterium labeling experiments showed this minor component to
arise through the thermal oxidation of the 2,3-carbon-carbon
bond of the side chain to yield the 2,3-enamine.
Cathinone, methcathinone, dimethcathinone, ethcathinone, and
diethylcathinone (diethylpropion) were separated by reversed-
phase liquid chromatography using a phenyl bonded stationary
phase and an acidic (pH 3) mobile phase. Methcathinone and
‘athinone do not interfere or cross-react in standard drug abuse
screening methods based on analysis by thin-layer chromatography
or immunoassay.
Introduction
Methcathinone (ephedrone, c-methylaminopropiophenone,
“CAT’) isan amphetamine-type drug of abuse that was first dis-
covered in clandestine drug samples obtained in the Upper
Caren
az Alabama Reece abortores, ne, Souh Hl Seek, Montgoneny
‘abana 6103
*uthort whom conepondence shouldbe asd
552
Peninsula of Michigan in the early 1990s (1). More recently,
this drug has been encountered in other portions of the United
States, including the state of Washington (1). Furthermore,
methcathinone abuse has been reported (2) in other coun-
tries for some time, particularly in the former Soviet Union
where it is known as “Jeff. In an attempt to prevent the more
widespread manufacture and use of methcathinone in the
United States, it was recently (October 15, 1993) placed into
Schedule I of the Federal Controlled Substances Act (1).
Methcathinone (Chart 1) is the N-methyl analogue of the
natural product cathinone (‘khat”), a psychoactive alkaloid
present in the leaves of the khat shrub, Catha edulis (3,4).
‘The khat plant grows in Eastern Africa and the Arabian Penin-
sula, and its leaves are distributed to countries throughout
the region, including Somalia. The leaves are chewed to release
cathinone, which produces stimulant-like effects similar to
amphetamine. It appears that only fresh khat leaves contain the
active alkaloid, thus leaves must be imported daily to provide
a continuous supply of the drug. This factor has historically re-
stricted the availability of the khat leaves. However, with in-
creased transportation efficiency, khat leaves have achieved
wider distribution to more distant countries with significant
African and Arab immigrant populations. Although khat use
0
NRR’
CHs
=R'=H: CATHINONE
=H, R'=CHy: METHCATHINONE
: DIMETHCATHINONE
R'=CH,CHy: ETHCATHINONE
=CH,CHy: DIETHYLPROPION
Chart 1, Structure of methcathinone and related compounds.Journal of Chromatographic Science, Vol. 32, December 1994
does not appear to be a significant problem in the United
States, the synthetic analogue, methcathinone, has been en-
countered with greater frequency, suggesting the potential for
future epidemic abuse (1). The abuse of this drug, like cathi-
none, appears to result from its ability to produce stimulant ef-
fects by neurochemical mechanisms similar to those of am-
phetamine and methamphetamine (4,5).
Methcathinone was originally investigated as a potential
pharmaceutical agent to treat obesity and the symptoms of
depression in the 1950s and 1960s (6). However, as a result of
its severe side effect profile and high addiction potential, meth-
cathinone was never marketed in the United States. Itis a syn-
thetic derivative of cathinone prepared from ephedrine by di-
rect oxidation with dichromate or permanganate (2,6).
Ephedrine is widely marketed in the United States as an “over-
the-counter” dietary agent and stimulant or energy drug (“pep
pills”). Thus clandestine laboratory operators can obtain
ephedrine without restriction and have developed methods to
convert it to methcathinone using common chemicals such as
battery acid, drain cleaner, and epsom salts (1,7).
Like methamphetamine, methcathinone contains a chiral
carbon at the 2-position of the side chain and therefore can
exist in two enantiomeric forms. Preliminary pharmacological
evidence indicates that stimulant activity resides primarily in
the S-(-)-isomer of methcathinone (8). Although the litera-
ture (1,6) suggests that S-(-)-methcathinone can be synthe-
sized stereospecifically by oxidation of 1,2S-ephedrine, no
HoH
NHCHS NHCHy
¢
Won,
K,0r207
une,
HoH
NHCHs x? x
So chy #
Scheme 1. Synthesis of methcathinone by oxidation of ephedtines and
pseudoephedrnes.
direct evidence confirming the stereochemical composition
of the methcathinone products is provided in these reports. Gas
chromatographic and mass spectral data have been reported for
methcathinone, but there are no reports on the stability of
methcathinone during these analytical procedures. In our pre-
liminary studies, methcathinone decomposition was observed
during attempts at gas chromatographic-mass spectrometric
(GC-MS) analysis. In this report, we describe the thermal de-
composition products of methcathinone and designer ana-
Jogues as well as their liquid chromatographic (LC) separation
and the stereochemical aspects oftheir synthesis.
Experimental
S-(-)-N-(Trifluoroacetyl)prolyl chloride derivatization
Approximately 1 mg of each methcathinone enantiomer or
2 mg of racemic methcathinone was dissolved in 10% aqueous
sodium bicarbonate. This solution was extracted with approx-
imately 1 mL of chloroform, S-(-)-N-(Trifluoroacetyl) prolyl
chloride (TPC) reagent (250 pL of 1.0M solution in methy-
lene chloride) (Aldrich Chemical; Milwaukee, WI) was added to
the chloroform solutions and allowed to react for 10 min at
room temperature. The solution was washed with 0.5N NaOH
to remove unreacted TPC, filtered, and placed in a 2-mL capped
autosampler vial for injection into the GC-MS.
Gas chromatography and mass spectrometry
GC-MS analyses were performed using a Hewlett-Packard
5970B mass selective detector (Wilmington, DE). All meth-
cathinone samples and methcathinone-TPC derivatives, ex-
cept that shown in Figure 7, were introduced into the mass
spectrometer via a GC equipped with a 12-m x 0.20-mm i.d
fused-silica column with a 0.33-pm film thickness of methyl-
silicone (HP-1, Hewlett-Packard). For the methcathinone~TPC
derivatives, the column temperature was held at 70°C for 1 min
and programmed to 200°C at arate of 7.5°C/min and from 200
to 275°C at a rate of 10°C/min. For the underivatized meth-
cathinone samples (except Figure 7), the column temperature
was held at 70°C for 2 min and programmed to 170°C ata rate
of 10°C/min and from 170 to 275°C at a rate of 25°C/min with
ahold time of 2 min. The injector port temperature was 175°C.
°
NHCHS
W Yow,
°
on™
chy #
d
Aer,
(s-TP¢)
(Pa.
och
i
W Yew, 0 oer
och
A W :
ZS MS ers | min
‘Scheme 2, Derivatization of methcathinone enantiomers with $--Ns(tifluoroacetylprolyl chloride
The sample shown in Figure 7 was intro-
duced via a GC equipped with a 10-m x
0.20-mm i.d, fused-silica column with a
+ | 0.33-ym film thickness of 5% cross-linked
phenylmethylsilicone gum phase (DB-5,
J&W; Folsom, CA). The column tempera-
ture was held at 40°C for 1 min and then
programmed to 150°C at a rate of 15°C/min
and from 150 to 250°C at a rate of 25°C/
Liquid chromatography
The liquid chromatograph (LC) consisted
of a Laboratory Data Control Constametric
3000 pump (Rivera Beach, FL), 3100 Spec-
553Journal of Chromatographic Science, Vol. 32, December 1994
‘Abundance
‘4000000 A
3000000
2000000
1000000
12 « 16 18 20 22 26
Tina (in)
Abundance
000000
3000000
2000000
1000000
12 1 16 18 20 2 2
Time in)
Abundance 20,720 min
166 c
eoo000
700000
00000
500000
400000
300000
200000
251
7 105
100000 ul 148
°
223 a 356
100 200 300
Auras
‘s000000 D
3000000
2000000
1000000
2 1" 16 8 20 2 28
Tine (rin)
Figure 1. Gas chromatographic and mass spectral analysis of methcathinone-TPC derivatives: A chromatogram of 1R,2S-ephecrne; B, chromatogram of 15,2R-
ephedrine; C, mass spectrum of methcathinone-TPC; D, chromatogram from racemic ephedrine.
554
Alejandra B Cardillo Et Al - Expression of Brugmansia Candida Hyoscyamine 6beta-Hydroxylase Gene in Saccharomyces Cerevisiae and Its Potential Use As Biocatalyst
Nurussaba Khanam Et Al - Organogenesis, Differentiation and Histolocalization of Alkaloids in Cultured Tissues and Organs of Duboisia Myoporoides R. Br.
Suvi T. Hakkinen Et Al - Enhanced Secretion of Tropane Alkaloids in Nicotiana Tabacum Hairy Roots Expressing Heterologous Hyoscyamine-6beta-Hydroxylase
Severine Mahon Et Al - Role of A Striatal Slowly Inactivating Potassium Current in Short-Term Facilitation of Corticostriatal Inputs: A Computer Simulation Study
Mariela F. Perez, Francis J. White, and Xiu-Ti Hu - Dopamine D2 Receptor Modulation of K + Channel Activity Regulates Excitability of Nucleus Accumbens Neurons at Different Membrane Potentials
Jay R. Gibson Et Al - Role For The Subthreshold Currents ILeak and IH in The Homeostatic Control of Excitability in Neocortical Somatostatin-Positive Inhibitory Neurons
Rishikesh Narayanan and Daniel Johnston - The H Channel Mediates Location Dependence and Plasticity of Intrinsic Phase Response in Rat Hippocampal Neurons