NIGER DELTA UNIVERSITY

WILBERFORCE ISLAND, AMASSOMA

FACULTY OF PHARMACY

DEPARTMENT OF PHARMACEUTICAL AND MEDICINAL

CHEMISTRY

THE CHEMISTRY OF MORPHINE, QUININE AND COCAINE

Course Code: PCH 822

Course Title: Natural Product Chemistry

By: THELMA AGBOLO

Submitted to: DR DIEPREYE ERE

Date: 9TH August,2021

Table of Contents

1. MORPHINE........................................................................................................................2

1.1 MORPHINE DERIVATIVES.....................................................................................2

1.2 PHYSIO-CHEMICAL PROPERTIES OF MORPHINE............................................3

1.3 SYNTHESIS OF MORPHINE....................................................................................4

1.3.1 Gates Synthesis....................................................................................................4

1.3.2 Rice Synthesis......................................................................................................4

1.4 STRUCTURE ACTIVITY RELATIONSHIP (SAR).................................................5

2 COCAINE...........................................................................................................................5

2.1 PHYSIO-CHEMICAL PROPERTIES OF COCAINE...............................................6

2.2 REACTIONS OF COCAINE......................................................................................7

2.3 SYNTHESIS OF COCAINE.......................................................................................8

2.4 STRUCTURE ACTIVITY RELATIONSHIP (SAR) OF COCAINE........................8

3. QUININE............................................................................................................................9

3.1 PHYSICO-CHEMICAL PROPERTIES OF QUININE...........................................10

3.2 REACTIONS OF QUININE.....................................................................................11

3.3 SYNTHESIS OF QUININE......................................................................................12

3.4 STRUCTURE ACTIVITY RELATIONSHIP..........................................................12

REFERENCE.......................................................................................................................13
1. MORPHINE

Morphine was isolated by Serturner (1805) from opium, and it was the first plant base to be
isolated. Its structure was proposed in 1925 by Guillard and Robinson and total synthesis
accompanied by Gates and Tschud in 1952, while Kalvoda and co-workers established its
absolute configuration in 1955.

The natural substance is (-)- morphine while the (+)- isomer has no analgesic activity. It is
insoluble in water, soluble in base (phenolic hydroxyl group present). It forms water-soluble
salt a with most acids and is used preferably as the sulphate and hydrochloride. It has a very
high ability to relieve pain, but its dependence liability has limited its clinical use.

Figure 1: Structure of Morphine

Asymmetric centres are indicated in C-5, 6, 9, 13 and 14 only with the configuration 5R, 6S,
9R, 13S and 14R respectively. Inversion of OH configuration at C-6 gives isomorphine,
which has increased analgesic potency.

Analgesics with low or virtually no abuse potential and with limited central and peripheral
side effects have been prepared.

1.1 MORPHINE DERIVATIVES

The morphine molecule can be altered in a variety of ways; its structural modification has
produced various derivatives with varying degree of activity compared to morphine. The
phenolic group in morphine is very important; however, analgesic activity appears to depend
on a p-phenyl-N-alkyl piperidine moiety in which the piperidine ring is in the chair form and
is perpendicular to the aromatic ring. The various derivatives include

1. Methylmorphine (codeine): is prepared by the methylation of the phenolic hydroxyl

group of morphine.

2. Dimethylmorphine (thebaine). Methylation of both hydroxyl groups of morphine

produces thebaine

3. Diacetylmorphine (heroin). Acetylation of both alcoholic and phenolic hydroxyl

groups of morphine gives diacetylmorphine

4. Dihydromorphinone (dilaudid). It is obtained from morphine by the oxidation of the

alcohol hydroxyl group to a ketone and the reduction of the C7-C8 double bond.

5. Methyldihydromorphinone or hydrocodone (metopone). It is prepared by the

conversion of the phenolic hydroxyl group of dihydromorphinone to methoxy group.
Other derivatives include the azido derivatives, ethylmorphine,
dihydrohydroxylmorphinone and dihydrohydroxylcodeinone

Thebaine
Diacetylmorphine

methylation
acetylation

ethylation methylation
Ethylmorphine MORPHINE Codeine
Codeinone
CrO3
H2/Pt2O

Normorphine methylation
Dihydromorphinone Dihydrocodinone

Figure 2: Derivatives of Morphine

1.2 PHYSIO-CHEMICAL PROPERTIES OF MORPHINE

The physio-chemical properties of morphine are divided into two.

 Molecular formula C17H19O3N

 Molecular weight 285.34g/mol
 1. Morphine is a white crystalline powder, odorless or almost odorless.
2. Morphine salts are soluble in ethanol but are insoluble in ether and chloroform.
3. The saturated or hydrated forms of morphine are not very soluble in water or lipids
4. The salts of morphine such as morphine hydrochloride and morphine sulfate are very
soluble in water

1.3 SYNTHESIS OF MORPHINE

1.3.1 Gates Synthesis

Gates total synthesis of morphine provided a proof of the structure of morphine proposed by
robinson in 1952.

Figure 3: Gate Synthesis of Morphine

1.3.2 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
 Figure 4: Rice Synthesis of Morphine

1.4 STRUCTURE ACTIVITY RELATIONSHIP (SAR)

1 A basic centre able to associate within anionic site on the receptor surface.
2 A flat aromatic structure, coplanar with the basic centre, allowing for Vander waal’s
bonding to a flat surface on the receptor site to reinforce the ionic bonds.
3 A suitably positioned, projecting hydrocarbon moiety forming a three-dimensional
geometric pattern with the basic centre and the flat aromatic structure.
4 Removing or introducing a ring system. This results to an increase in size, shape changes
and stability of structure with the substitution of C=C double bond.

2 COCAINE
 CHCOOCH3

NCH3 CHOCOC6H5

O
O CH3

A N CH3 B O
O

2 - M e t h o x y c a r b o n y l T r o p a n e - 3 - y l- B e n z o a t e

Figure 5: showing the structure of Cocaine.

Cocaine is known as a tropane alkaloid and a stimulant substance derived largely from the
leaves of Erythroxylum coca and Erythroxylum novogranatense, which are both coca species.
It is most often used as a euphoriant and recreational drug. Cocaine can be snorted, heated
until sublimated, inhaled, or dissolved and infused into a vein after being obtained from coca
leaves. Cocaine in its purest form is a white, pearly product. Cocaine appearing in powder
form is a salt, typically cocaine hydrochloride. Street cocaine is often adulterated or cut with
talc lactose sucrose glucose mannitol inositol caffeine procaine phencyclidine phenytoin
lignocaine strychnine amphetamine or heroin. The molecular formula of cocaine is
C17H21NO4, with a Molecular weight of 303.35g/mol. A melting point of 98°C and boiling
point 187°C.

Total extraction of bases from plant leaves is followed by acid hydrolysis of ester alkaloid to
achieve total Ecgonine content in commercial cocaine manufacturing (cocaine). Ecgonine is
purified and then esterified with methanol and benzoic acid to make cocaine.

2.1 PHYSIO-CHEMICAL PROPERTIES OF COCAINE

1. Cocaine hydrochloride is water, ethanol, and chloroform soluble. Cocaine
hydrochloride is ether insoluble, and fixed oil insoluble.
 2. Cocaine is a colourless to white crystals or white powder
3. The cocaine alkaloid freebase is colourless transparent crystalline substance
4. Monoclinic tablets from alcohol

2.2 REACTIONS OF COCAINE

 Sodium bicarbonate NaHCO3, common baking soda) is a base used in the preparation
of crack, although other weak bases may substitute for it. The net reaction when using
sodium bicarbonate is

Coc-H+Cl− + NaHCO3 → Coc + H2O + CO2 + NaCl

 With ammonium bicarbonate

Coc-H+Cl− + NH4HCO3 → Coc + NH4Cl + CO2 + H2O

 With ammonium carbonate:

2(Coc-H+Cl−) + (NH4)2CO3 → 2 Coc + 2 NH4Cl + CO2 + H2O

 Cocaine undergoes hydrolysis to produce Ecgonin, methanol and benzoic acid upon
heating in the presence of concentrated sulfuric acid.

O
O
O CH3
O
O CH3
H 2S 0 4 OH
N CH3 OH + C H 3O H +
N CH3 O
O H 20 ,to

Methanol in turn reacts with benzoic acid (esterification) to give benzoic acid methyl
ester which gives a characteristic odour. On cooling and standing the benzoic acid
may crystallize out.

O O
H 2 S O 4
OH O CH3
+ C H 3 O H
-H 2 O

 Cocaine hydrochloride reacts with potassium dichromate solution.

 O O
O CH3 O CH3
K 2C r2O 7
XHCL
2 N CH3 O + N CH3 2-
H O C rO 4
O O

+ 2KCL

2.3 SYNTHESIS OF COCAINE

Ecgonine is esterified with methanol followed by benzoylation to yield cocaine
CHCOOCH3
CHCOOH
CH3OH

NCH3 CHOCOC6H5
NCH3 CHOH

C6H5COOH

Ecgonine (-) COCAINE

2.4 STRUCTURE ACTIVITY RELATIONSHIP (SAR) OF COCAINE

1. The hydrophobic part is used to esterify aromatic acids. Its advantage is its ability to
form salts with inorganic acids producing water soluble compounds.
2. The propylene group provides the most active compounds
3. Introduction of electron-donating groups in the ortho or para position of the ring
increases conjugation and the binding of drug to the receptor prolonging the action.
The opposite occurs for electron-withdrawing groups
4. It is observed that benzocaine which lacks the basic aliphatic amine has the potent
local anaesthetic activity.
5. The lipophilic portion is essential for activity.
6. Replacement of the C-2 ester group by vinyl argues against hydrogen- bonding and
provides an esterase-resistant and high-affinity cocaine.
7. The carbonyl group must be conjugated with an aromatic nucleus whereas reversed
have no local anaesthetic activity.
8. The esters of cinnamomic acid are more active than those of phenyl acetic acid due to
interruption of the extended conjugation by methylene group between the aromatic
ring the carbonyl group.
 9. The branching with small alkyl group around the ester function (meprylcaine) also
hinders esterase catalysed hydrolysis prolonging the duration of action.

3. QUININE

Quinine is an alkaloid, a naturally occurring chemical compound that is found in the highest
concentration in cinchona bark. When prepared from the crude bark, the powder of cinchona is
alkalinized and then extracted with a hot high boiling petroleum fraction to isolate the alkaloid.
Quinine is basically used for the treatment of a simple malaria, a disease caused by parasites.
Malaria-causing parasites are usually transmitted to humans through mosquito bites.

Figure 6: Structure of Quinine

The molecular formula of Quinine is C20 H24 N2 O2 and its molecular weight is 324.424 g·mol−1
and its melting point is 177 °C

Quinine is a basic amine that comes in the form of a salt. The hydrochloride, dihydrochloride,
sulfate, bisulfate, and gluconate are some of the current formulations.

Quinine base in various salts

 Name Quinine base equivalence

Quinine base 100 mg

Quinine bisulfate 169 mg

Quinine dihydrochloride 122 mg

Quinine gluconate 160 mg

Quinine hydrochloride 111 mg

Quinine sulfate dihydrate 121 mg

[(quinine)2H2SO4∙2H2O]

3.1 PHYSICO-CHEMICAL PROPERTIES OF QUININE

1. Quinine dihydrochloride is a white or almost white powder.

2. Quinine hydrochloride is a fine colourless silky needle always grouped in clusters.

3. Quinine sulphate is a white crystalline powder or colourless needles.

4. All quinine salts are very bitter

5. Quinine dihydrochloride is very soluble in water, quinine hydrochloride is soluble in

water and quinine sulphate is slightly soluble in water and sparingly soluble in boiling
water.

6. Quinine hydrochloride and quinine dihydrochloride are freely soluble in ethanol and
sparingly soluble in ethanol of quinine sulphate.
3.2 REACTIONS OF QUININE
 As a weak organic base, quinine salts react with alkaloidal reagents to produce
coloured precipitate, picric acid for example.

1. HO
– HO
O O CH3 –
CH3 OH CH2 O – O
CH2 + + O
N N – O + +
O O O + N N
NH –
N O O
+ NH
+
2x
N
+
– N +
O O – N
O O

 Quinine salts are of weak organic base and strong mineral acid, thus upon addition of
alkaline hydroxide solution precipitation of organic base is formed.

HO HO Br HO OH
CH3 O
CH2 B r2 Br NH
O O N H 4O H HN HO

N N N

N N N
H2O
T h a lle o q u in

HO HO
CH3
CH2 CH3
O CH2
+ - O
NH 2cl + 2N aO H
N
+ + 2 N a C L + H 2O
NH
N

 Thalleioquinine test. Quinine salts when reacted with bromine water and ammonium
hydroxide solution gives a green coloration which indicates the presence of
thalleioquinine.
 Quinine sulphate salt reacts with potassium sodium tartarate to produce precipitation.

2 OH
O K HO HO

Na O
CH3
CH2
CH3
CH2
O
+ 2 H 2S O 4
O O
N
O N
N
N
2 O
2 OH
+ K 2S O 4 + N a 2S O 4
3.3 SYNTHESIS OF QUININE

Figure 7: Showing the structure of synthesis of Quinine

3.4 STRUCTURE ACTIVITY RELATIONSHIP

1. Activity usually enhanced by the introduction of a halogen at position 8
2. Asymmetry at position 3 and 4 is not essential for antimalarial activity
3. Replacement of methoxyl group by halogen especially chlorine increases activity
4. Presence of methoxy group in quinine is not necessary for activity
5. Modification of the secondary alcohol at C-9 through oxidation, esterification,
diminishes activity
6. A further increase in activity results in the introduction of a phenyl group at position 2
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