Alkaloids: alkaloids as pharmaceutical raw materials, opium and its analogue, synthesis of ephedrine, clinical comparison of ephedrine and epinephrine.

1. and
PHARM 3127: Medicinal Chemistry
Alkaloids
Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh

2. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 1
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Alkaloids
Syllabus for Alkaloids: alkaloids as pharmaceutical raw materials, opium and its analogue,
synthesis of ephedrine, clinical comparison of ephedrine and epinephrine.
Alkaloids:
Alkaloids may be defined as basic nitrogenous compounds which occur
abundantly in the plant kingdom. They contain one or more nitrogen usually in a
heterocyclic ring and have a marked physiological action on man & animals. The
nitrogen may exist as primary (1° amines), secondary (2° amines) or tertiary (3° amines)
amine. These compounds are basic but the degree of their basicity depends on the
structure of the molecule and presence and location of other functional groups.
Alkaloids as pharmaceutical raw materials:
Alkaloids are natural products. They are the secondary metabolites of plant.
Their structure is diverse varying from simple to very complex structure and their
activity is also highly selective based on the structure. For example-
Tyrosine
Tyrosine
+
Norlaudanosoline
Reticuline
Salutaridine
Thebaine
Codeine
Morphine
Papaverine
H2C
NH2
H
COOH
HO
H2C
NH2
H
COOH
HO
NH
OH
OH
HO
HO
OMe
OMe
MeO
MeO
O
HO OH
N
CH3
O
MeO OH
N
CH3
O
MeO OMe
N
CH3
N
Md.
Imran
Nur
Manik

3. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 2
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
The difference between morphine and codeine is that codeine contains a methoxy
group in place of phenolic hydroxyl group. Morphine is an analgesic and it is 10 times
more potent compare to codeine. But codeine is mainly used as anti-tussive drug. It has
mild analgesic.
Again thebaine has structure similar to morphine and codeine (both the hydroxyl
groups are replaced by methoxy groups). But thebaine is neither analgesic nor anti-
tussive and it is mainly used as CNS stimulant.
Thus we can see that the simple molecular modification of principle compound
can give variation of pharmacological action and thus suit the need of different diseases.
So it is easily understandable that nature can give us idea of designing drug molecules
for different indications.
Opium alkaloids:
Opium:
It is the air dried milky exudates
obtained by incising the unriped
capsules of poppy plant (Papaver
somniferum Linn. of Papaveraceae
family).
The plant poppy is an annual herb
with large, showy, solitary flowers
having color of pink to purple.
Geographical source:
The plant is indigenous to Asia
Minor. The plant poppy is cultivated in
many countries but legal opium
production is not permitted in all
countries.
Constituents:
More than 30 (23 according to
FA) alkaloids are found in opium. The
two principle types of alkaloids
present in opium are –
1. Alkaloids containing partially hydrogenated phenanthrene nucleus:
Examples include morphine, codeine, thebaine etc which act primarily on the CNS
and produce stimulation or depression as well as smooth muscle contraction.
2. Alkaloids having 1-benzyl-isoquinoline structure: Example Narcotine,
Papaverine. They have little CNS action.
Md.
Imran
Nur
Manik

4. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 3
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
The most important are the alkaloids
1. Morphine: It is the most important opium alkaloid. It is a phenanthrene derivative
containing an alcoholic and phenolic OH group. Morphine and its salts occur as
white silky crystals, odorless and having a bitter taste. They are classified as
narcotic analgesics and are strong hypnotic and narcotic. Their use tends to induce
habit formation as well as common side-effects as nausea, vomiting and constipation.
2. Codeine: It is the most widely used opium alkaloid. It is obtained from opium, or by
methylation of morphine or by appropriate reduction and demethylation of thebaine.
If methyl group replaces the hydrogen of phenolic OH in morphine it becomes
codeine.
The drug and its salts are narcotics and antitussives. They are used as sedatives
especially in allaying coughs. Its action is similar to that of morphine but is less toxic.
Heroin: Diacetylmorphine or heroine is formed by acetylation of morphine, where the
hydrogen atoms of both the phenolic and alcoholic hydroxyl groups are replaced by
acetyl groups. Its action is similar but more pronounced than that of morphine. Due to
its potency and the danger of habit formation it is not used in medicine.
3. Noscapine
4. Thebaine
5. Papaverine
Also contains alkaloids like
i. Narceine, ii. Protopine, iii. Laudanine, iv. Codamine, iv. Cryptopine,
v. Lanthopine , vi. Meconidine
Md.
Imran
Nur
Manik

5. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 4
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Ephedrine:
Introduction:
Ephedrine is an Alkaloidal amine having sympathomimetic action.
Its action is similar to adrenaline but there are some differences.
Ephedrine can be extracted from stems of various species of
Ephedra or it can be chemically synthesized.
Chemical synthesis:
1. It is synthesized from benzaldehyde by condensing with
nitroethane. The corresponding compound in then reduced.
The L-isomer of the reduced compound is then methylated to obtain ephedrine.
CHO OH
NO2
CH3 CH3
NH2
OH
OH
CH3
H
N
CH3
MeIMethylation
2-methyl-2-nitro-1-
phenylethanol
[H]
2-methyl-2-amino-1-
phenylethanol
Benzaldehyde
EtNO2
Ephedrine
2. Benzaldehyde is fermented with glucose using yeast. The fermentation of glucose
leads to pyruvic acid formation with is condensed with benzaldehyde. The condensed
compound is hydrogenated in presence of methylamine to yield ephedrine.
CHO
Benzaldehyde
Glucose
Yeast
H3C
O
COOH
Pyruvic acid
OH
CH3
O
OH
CH3
H
N
CH3
Phenyl-1-hydroxypropanone-2
Condensation
CH3NH2
(H2)Pt
Ephedrine
Md.
Imran
Nur
Manik

6. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 5
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Comparison with epinephrine:
Criterion Ephedrine Epinephrine
Route of
Administration
Effective in oral route Must be given in IV route
(except when used as inhaler
for asthmatic attack)
Duration of
action
Prolonged Comparatively shorter
Onset of action
Slower (thus it is more suitable
more chronic asthma and colds)
Comparatively rapid
Potency Comparatively less Greater than ephedrine
Blood-Brain-
Barrier
penetration
Greater penetration Penetration is less
CNS activity Greater CNS activity Comparatively less active
Vasoconstriction
Stronger vasoconstriction Comparatively lower
vasoconstriction property.
Tolerance Possible Usually doesn’t occur
Structure
H
C
OH
CH
CH3
H
N
CH3
Ephedrine
H
C
OH
C
H2
H
N
CH3
HO
HO
Epinephrine
Md.
Imran
Nur
Manik

7. Natural Products and Secondary Metabolites: ALKALOIDS
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 6
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Papaverine:
Introduction: Papaverine is a smooth muscle relaxant. It exerts antispasmodic action on
blood vessels, thus it relieves arterial spasm caused by acute vascular occlusion. It can
be given orally.
Chemical synthesis: Below the synthesis of Papaverine is shown. This is known as
Pictet-Gams synthesis.
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
O
CH3
O
NOH
H3CO
H3CO
O
NH2
CHO
OH
OCH3
CHO
OCH3
OCH3
HOHC
OCH3
OCH3
CN
CH2COOH
OCH3
OCH3
CH2COCl
OCH3
OCH3
CH3COCl
AlCl3
C5H11ONO C2H5ONA
C2H5OH 75%,RT,
,
,
SnCl2
HCl
RT
(CH3)2SO4 HCN 1. HI
2. Hydrolysis
PCl5
KOH
OC
NH
H2C
RT
H3CO
H3CO
O
OCH3
OCH3
Na-Hg, H2O
50 C°
OC
NH
H2C
H3CO
H3CO
OH
OCH3
OCH3
P 2
O 5
, Xylene
Reflux
N
H2C
H3CO
H3CO
OH
OCH3
OCH3
Papaverine
Md.
Imran
Nur
Manik