INTRODUCTION

Natural products have been a source of medicinal agents for

thousands of years. Impressive number of modern drugs derived
from natural products. Today, natural products are one of the main
interests for research directed towards drug design and discovery. It
also has provided considerable value to the pharmaceutical industry
over the past half century. In particular, the therapeutic areas of
infectious diseases and oncology have benefited much from
numerous drug classes derived from natural form and it is used as
template for synthetic modification.
The use of natural products as medicine has initiated the
isolation of active compounds. The first commercial pure natural
product introduced for therapeutic use is generally considered to be
the narcotic morphine. Morphine is actually a form of alkaloids.

IUPAC: (5,6)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol
Alkaloids are natural organic nitrogen-containing bases found
mainly in plants. Opium alkaloid is natural compound that have
been extracted from opium-sticky exudate from poppy (PapaVer
somniferum). Opium contains a complex mixture of merely twentyfive alkaloids. The principal alkaloid in the opium and the one
responsible for analgesic activity is known as morphine. Morphine is
a bitter white crystalline compound.
In early 1800s, Morphine was first isolated in pure form from
the dried poppy resin by Friedrich W. Sertrner. Sertrner named the
compound as morphium after Morpheus; the Greek god of dreams,
for its tendency to cause sleep; in therapeutic doses it is an
analgesic. By right it is perhaps the only chemical that has been
named after the Greek god.
Morphine was isolated and purified on a commercial scale in
1833 by chemists at Macfarlane & Co. (now known as MacfarlaneSmith) in Edinburgh. Functional groups of morphine had been

identified by 1881 but it took many years to really establish the

structure of morphine. The structure elucidation of morphine was
completed by Sir Robert Robinson in 1925. The full synthesis of
morphine was achieved in 1952. This synthesis took another twentyseven years.
Eventhough the structure of morphine obtained later, but its
analgesic properties were recognized and already applied to
medicine. Morphine is far more effective than crude opium as
analgesic since morphine is in the pure form. Sadly, morphine gives
the risks of addiction, tolerance and respiratory depression

DISCUSSIONS
ORIGINAL SOURCES

Morphine is the most abundant opiate in opium. It is the

principal alkaloid of opium. Opium is the name of latex produced
within the seed pods of the opium poppy, PapaVer somniferum L., or
P. album Mill, PapaVeraceae.
The plant is believed to have evolved from a wild strain,
PapaVer setigerum, which grows in coastal areas of the
Mediterranean Sea. Through centuries of cultivation and breeding
for opium, the species somniferum evolved.
Now, P. somniferum is the only PapaVer used to produce
opium. These opium contains morphine, codeine, noscapine,
papaverine and thebaine. They are used as analgesics but Thebaine
is the only one without analgesic effer but is the great
pharmaceutical value due to its use in production of semisynthetic
opioid morphine analogues such as oxycodone (Percodan),
dihydromorphenone (Dilaudid) and hydrocodone (Vicodin).
Morphine also can be found in normal brain, blood and liver
tissue.

USE OF THE DRUG

Morphine is a narcotic; acts directly on the central nervous
system (CNS). Besides relieving pain, it also impairs mental and
physical performance, relieves fear and anxiety and produces
euphoria. It also decreases hunger, inhibits the cough reflex,
produces constipation and reduces the sex drive; in women it may

interfere with menstrual cycle.

Morphine was first used as medicinally as a painkiller and also
as a cure for opium addiction. Morphine is highly addictive. It was
used during the American Civil War as a surgical anesthetic and was
sent home with many wounded soldiers for relief of pain.
Unfortunately, over 400,000 people had the army disease;
morphine addiction at the end of the war. The Franco-Prussian War
in Europe also had a similar effect.
Tolerance (the need for higher and higher doses to maintain
the same effect) and physical and psychological dependence
develop quickly. Withdrawal from morphine will cause nausea,
tearing, yawning, chills, and sweating lasting up to three days.
Morphine crosses the placental barrier. It is not advisable for
pregnant and breastfeeding women to take morphine as it will affect
infant.
Today morphine is used medicinally for severe pain, cough
suppression, and sometimes before surgery. It is seldom used illicitly
except by doctors and other medical personnel who have access to
the drug. It is injected, taken orally or inhaled, or taken through
rectal suppositories. Methadone is a useful treatment in curing
morphine addiction.

PRODUCTION OF MORPHINE
Legal growing of opium for medicinal use currently takes place
in India, Turkey and Australia. Two thousand tons of Opium produced
annually . These Opium is then supplied to the world with the raw
material needed to make medicine. The legal opium shipping centre

is known as Mallinckrodt; one of the pharmaceutical companies that

has license to deal in legal poppy production. It uses crates to ship
its poppy products around the world.
The problem faced in the production of morphine is mainly
regarding the illegal production of morphine itself. Currently, there
are three main sources for illegal opium; Burma, Afghanistan and
Colombia. Opium is an ideal trade products as it is in great demand,
very profitable to produce and the products take up little space. It
can easily be moved from one country to another within days or a
few weeks with modern transportation. Opium has a long and stable
shelflife. This will allow the products to be stored for long periods of
time.
TIMELINE OF MORPHINE DEVELOPMENT
1803
1833
1925
1952
1968

Isolation and purification

Isolation and purification in commercial scale
Chemical structure elucidation by Sir Robert Robinson
Total synthesis
Structure confirmed by X-ray

ISOLATION OF MORPHINE
RAW OPIUM
1. Reflux with NaOH in MeOH
2. Filtration

PRECIPITATE MeOH EXTRACT

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1. Add filtered aid

2. Distill out MeOH
MeOH
MeOH
EXTRACT

FILTER
AID

MeOH
EXTRACTION

TOTAL ALKALOIDS
1. Add 1.0 M NaOH solution
2. Stir for 10 minutes
3. Filtration
FILTRATE

1. Add NaOAc
2. Filtration

PRECIPITATE ON
FILTERED AID
PRECIPITATE

FILTRATE
TOLUENE
EXTRACTS

Adjust pH to 9 with AcOH

AQUEOUS PHASE

MOTHER
LIQUOR

MORPHINE
PRECIPITATE

STRUCTURE ELUCIDATION
In 1925, Sir Robert Robinson has completed the structure
elucidation of morphine.
1
H-NMR of Morphine

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C-NMR of Morphine

IR of Morphine

Mass Spectroscopy of Morphine

SAR STUDIES

SAR investigation was conducted to identify the role of each

functional group; the important parts of the molecule that is
essential to provide activity without affecting the basic skeleton of
the molecule.
The parts that were investigated are phenolic OH, 6-alcohol,
double bond at C-7/C-8, N-methyl group, aromatic ring, ether bridge
and stereochemistry.

From the SAR investigation, there are four important part for
binding at active sites which are the free phenolic group, aromatic
ring, N atom and it should not be charged to facilitate the passage
through blood brain barrier and lastly the stereochemistry; must
have correct enantiomer at C-14 and C-9.
TOTAL SYNTHESIS OF MORPHINE
Synthesis of morphine-like alkaloids in chemistry
describes the total synthesis of the natural morphinan class of
alkaloids that includes codeine, morphine, oripavine, and thebaine
and the closely related semisynthetic analogs buprenorphine,
hydrocodone, isocodeine, naltrexone, naloxone, nalbuphine, and
oxycodone.
The structure of morphine is not complex but the electrostatic
polarization of the adjacent bonded atoms that does not alternate
uniformly throughout the structure. It makes bond formation more
difficult and therefore it will complicate any synthetic pathway that
is applied to this molecule.
Marshall D. Gates, Jr. proposed the first morphine total
synthesis in 1952 and it remains a widely used example of total
synthesis. This synthesis took a total of 31 steps and give out 0.06%
overall yield. The dihydrocodeinone synthesis of Kenner C. Rice is
one of the most efficient and give out 30% overall yield in 14 steps.
Several other syntheses were reported, notably by the
research groups of Evans, Fuchs, Parker, Overman, Mulzer-Trauner,
White, Taber, Trost Fukuyama, Guillou, Stork, and Magnus.
i.

Gates Synthesis
Gates' total synthesis of morphine has proved the structure of
morphine proposed by Robinson in 1925. This synthesis of
morphine features one of the first example of the Diels-Alder
reaction in the context of total synthesis.

ii.

Rice Synthesis
The Rice synthesis follows a biomimetic route and is the most
efficient reported to date. A key step is the Grewe cyclization
that is analogous to the cyclization of reticuline that occurs in
morphine biosynthesis.

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BIOSYNTHESIS OF MORPHINE
Morphine is biosynthesized from the tetrahydroisoquinoline
reticuline. It is converted into salutaridine, thebaine, and oripavine.
The enzymes involved in this process are the salutaridine synthase,
salutaridine:NADPH 7-oxidoreductase and the codeinone reductase.
Researchers are attempting to reproduce the biosynthetic pathway
that produces morphine in genetically engineered yeast. In June
2015 the S-reticuline could be produced from sugar and R-reticuline
could be converted to morphine, but the intermediate reaction could
not be performed. In August 2015 the first complete synthesis of
thebaine and hydrocodone in yeast were reported, but the process
would need to be 100,000 times more productive to be suitable for
commercial use.

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SUMMARY
1. Morphine is an analgesic that naturally found in opium which
is a sticky exudate obtained from Poppy (PapaVer
somniferum).
2. Opium contains complex mixture of almost 25 alkaloids and its
major active component is morphine.
3. Morphine has high risks of addiction.
4. It can be obtained through extraction of raw opium.
5. Morphine was first isolated in pure form from the dried poppy
resin by Friedrich W. Sertrner in 1803.
6. Sir Robert Robinson completed the structure elucidation of
morphine in 1925.
7. The first total synthesis of morphine was deduced by Marshall
D. Gates, Jr. in 1952 known as Gates synthesis. This synthesis
proved the structure of morphine that has been proposed by
Sir Robert Robinson in 1925. Gates synthesis produced is low
yield.
8. The Rice synthesis is probably the most effective synthesis
since it produce high yield of morphine ; 30% yield.
9. Morphine is biosynthesized from tetrahydroisoquinoline
recticuline.
10.
From the SAR investigation, there are four important
part for binding at active sites which are the free phenolic
group, aromatic ring, N atom and it should not be charged to
facilitate the passage through blood brain barrier and lastly
the stereochemistry; must have correct enantiomer at C-14
and C-9.

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REFERENCES
1. P. R. Blakemore, J. D. White, Chem. Commun. 2002, 1159
1168
2. J. G. Hexem, M. H. Frey, S. J. Opella. J. Am. Chem. Soc., 1983,
105(18), 5717-5719
3. M. Gates, G. Tschudi, J. Am. Chem. Soc., 1956, 78 (7), 13801393
4. K. C. Rice, J. Am. Chem. Soc., 1980, 45 (15), 3135-3137
5. H. Rapoport, F. R. Stermitz, D. R. Baker, J. Am. Chem. Soc.,
1960, 82 (11), 2765-2772

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