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Alkaloids
•Typical alkaloids: are basic compounds
containing one or more N atoms (usually in
a heterocyclic ring) and usually has marked
physiological activity on man or animal.
•Pro-alkaloid or Amino-alkaloid: is termed
for compounds as ephedrine, colchicines
which lack one or more of the properties of
typical alkaloids.
• General properties of alkaloids:
• 1- Alkaloids are heterocyclic natural products
containing nitrogen usually derived from
amino acid. Compounds that contain nitrogen
in
aliphatic chain e.g. phenylalkylamines is
also considered.
• 2. Most alkaloids have a very bitter taste,
generally white solid (exception – e.g. nicotine
is a brownish liquid).
• 3. Many alkaloids are alkaline in nature, as
they possess either a primary, secondary or
tertiary amine group.
• 4. The alkaline (basic) characters of these
groups aid their extraction and purification.
They can be extracted from their sources by
treatment with acids (usually hydrochloric
acid or sulfuric acid, are used).
•
• 5. Some alkaloids may naturally exist as salts
[result from the reaction of a base with an acid
as oxalic, tartaric, meconic acid or quinic
acids].
• 6. Some alkaloids exist as quaternary amine
salts (in which a lone pair of electrons from
the nitrogen atom is used to form a bond with
another group e.g. methyl) and therefore
positive charge resides on the nitrogen atom
making this group neutral [neither basic nor
acidic].
Classification
-Biological activity (antispasmodics,
anticancer, antihypertensive,
psychoactive…..etc)
-Chemical structure
(nucleus containing nitrogen)
-Biosynthetic pathway
(the way they are produced in the plant)
6
According to Hegnauer's classification
(The type of nitrogen and the biochemical origin)
True alkaloids
Nitrogen in a
heterocyclic ring
Proto alkaloids
Don't have nitrogen in a
heterocyclic ring
Derived from amino acids
Pseudo alkaloids
Nitrogen in a
heterocyclic ring
Not derived from
amino acids7
Nitrogen in alkaloids concerning:
1- Number of nitrogen atoms:
• Alkaloids usually contain one nitrogen
atom. Certain alkaloids may contain more
than one up to 5 nitrogen atoms
Nicotine (2N atoms)
Ergotamine (5N atoms)
2.Type of amino group:
Nitrogen in alkaloids exists in the form of amine
A secondary
amino group
A primary
amino group
A quaternary
ammonium ion
A tertiary
amino group
Ephedrine
dl-nor-ephedrine
Nicotine
9
d-Tubocurarine
• 3.Basicity:
• a- a lone pair of electrons on N atom confer
basic character to the alkaloids
• b- The amines & alkaloids resemble NH3 in
chemical characters by forming salts with acids
without liberation of H2O to give the
corresponding amine or alkaloid hydrochloride
• c- In plants, alkaloids occur as free bases,
salts or N-oxides (N→O).
• d- Factors that may influence the degree of
basicity:
 The structure of the molecule e.g. Piperidine
alkaloids are more basic than pyridine
alkaloids
 The presence and position of other substituents and
functional groups e.g. Electron releasing groups (
alkyl) increase the basicity
 Electron withdrawal groups (carbonyl) decrease the
basicity e.g. ricinine
Therefore some alkaloids are Neutral or acidic as Colc
hicine others are Amphoteric due to Phenolic group
(Morphine) or carboxylic group (Narceine)
•Physical properties of alkaloids:
A-Solubility:
1- All alkaloidal salts are water soluble
except quinine sulphate.
2- Most alkaloidal bases are soluble in
organic solvents but are water insoluble.
3- Few alkaloidal bases are water soluble as
colchicines,
pilocarpine,
purine
bases,
quaternary alkaloidal bases as berberine
and tubecurarine.
4- Few alkaloidal bases are insoluble in
organic
solvents as morphine which is
insoluble in ether.
5- Some alkaloidal salts are soluble in organic
solvents as ephedrine HCl (soluble in CHCl3).
B- Isomerism:
Many
alkaloids
contain
one
or
more
asymmetric
carbon atoms in the
molecule
therefore show
optical
activity. In
general the (-)-levorotatory
isomer is more pharmacologically active
than (+)- dextrorotatory isomer. Example
:(-)-ephedrine is 3.5 folds more active than
(+)-ephedrine.
The
exception
is
(+)tubecurarine which is the active form.
Chemical properties of alkaloids:
I-Salt formation:
•



According to the nature of alkaloids
A-Basic alkaloids
Strong bases form salts with very weak acids
Weak bases require stronger acids
Very weak bases form unstable salts e.g. caffeine
• B-Amphoteric alkaloids
• Those containing phenolic or carboxylic groups
can form salts with both acids and alkalis
• C-Acidic alkaloids
• Do not form salts with acids e.g. colchicine
• II- Stability
A- Effect of heat
• Alkaloids are decomposed by heat, except caffeine
that sublime without decomposition
B- Effect of heat and light in presence of oxygen
• N-oxides (3ry amines) water-soluble
•
C- Effect of acids: hot dil. or conc. acids cause
remarkable changes:
 Dehydration e.g. morphine gives apomorphine
 Demethylation e.g. morphine gives codeine
 Hydrolysis as ester linkage e.g. reserpine& glucoalk
-aloid as solanine
D- Effect of alkalis
 Weak alkalis
• liberates alkaloid bases from their salts
and form salts with alkaloids which contain
carboxylic groups
 Strong alkalis
• As Sod hydroxides form salts with alkaloids
which contain phenolic groups, e.g. morphine
•
 Hot alkalis
 In Ester alkaloids as hydrolysis as in atropine
 In Alkaloids which contain lactone ring
opening lactone ring as in pilocarpine
III- Precipitation or micro-crystal formation
for testing alkaloids with certain reagents are
1- Mayer’s reagent (KHgI test solution)=Hg2I + KI +H2O
2- Wagner’s reagent (Potassium tri iodide)=I2+KI+H2O
3- Kraut’s reagent (Modified Dragendorf’s )
=BiNO3+I2+ KI + H2O.
4- Marm’s reagent (Potassium cadmium iodide test
solution )= CdI + KI + H2O.
5- Scheibler’s reagent (Phosphotungetstic acid)
= Sod tungestate + Di sodium hydrogen phosphate
Na2HPO4 +HiNO3 + H2O.
6- Mercuric Chloride
7- Platinic chloride
8- Gold chloride
9- Reinkate salt solution = Ammonium reinekate +
Hydroxylamine HCl, filter, store the filtrate in
refrigerator.
IV- Colour reaction with certain reagents:
Although those colour reactions are rather unspecific but are very sensitive
so micrograms of alkaloids are required to give the colour response.
a- Froed”s reagent (Sulphomolybdic acid)= Sod. Molybdate + H2SO4
(Freshly prepared).
b- Marqui’s reagent = 2-3 drops of HCOH + 3 ml Conc. H2SO4.
c- Mandalin’s reagent (Sulphovanidic acid) = Ammonium vanedate
+ H2SO4.
d- Erdman’s reagent = 10 drops of HNO3 +100 ml H2O + 20 ml Conc.
H2SO4.
e- Schaer’s reagent = one volume of H2O2 + 10 volumes of Conc. H2SO4
(Freshly prepared).
f- Modified Dragendorf’s reagent (K2BiI)
(A) = Bismuth sub nitrate + Acetic acid 20%
(B) 40% aqueous KI in H2O Then take 1 A+1B +10 H2O
• General Methods of Extraction
1. Extraction with water miscible (polar) solvents:
a. The alkaloids are extracted in the salt form by acidulated water
and
alcohol, the alkaloids especially quaternary bases as
berberine and
tubecurarine are extracted plus many
pigments, tannins, resins and
saponins..
b. The aqueous percolate is concentrated under vacuum and rendered
alkaline, the free alkaloid is liberated and maybe:
 Precipitated, filtered as morphine
 The aqueous solution is shaken in a separating funnel with organic
solvents as CHCl3, several times till exhaustion (indicated by the
last CHCl3 fraction on evaporation + HCl + Mayer's R gives no
yellowish white PPT.
2. Extraction with water immiscible (non-polar) solvents:
The powdered drug is pretreated with alkali to liberate the
free alkaloid base, extracted with ether or CHCl3. The CHCl3
extract is evaporated under vacuum to afford alkaloid extr.
3. Extraction of alkaloid for medico-legal purposes:
The Stas-Otto process is adopted for very small concentra
-tion of alkaloid. The drug is finely minced, acidified and
treated with alcohol. The aqueous extract is shaken with
petroleum ether for defatting . The aqueous extract is
evaporated to dryness under vacuum, tested for alkaloids
4. Extraction by steam distillation:
This method is applicable for :
- Steam volatile alkaloids as ephedrine
- Nonoxygenated liquid alkaloids as sparteine, nicotine
The powder is treated with fixed alkali, NaOH, Ca(OH)2 ,
steam
distilled, the alkaloid in the distillate is
prepared either:
a. Extraction with immiscible organic solvent (ether or
CHCl3)
b. Fixation of alkaloid by acid, the aqueous solution is
evaporated under vacuum to dryness, extracted with
hydroalcohol, filtered, basified with alkali to liberate
free bases, extracted with CHCl3, evaporated.
• Identification of alkaloids by:
1. Determination of m.p. for alkaloid base and its salts.
2. Solubility in different solvents.
3. Determination of crystallographic properties with
special alkaloid precipitants giving specific crystal
shape, visualized by microscope.
4. Colour reaction with special reagents.
5. Spectroscopic data.
6. Determination of specific rotation
7. Chromatographic techniques as PC. TLC, GC, HPLC,
…….
Quantitative determination of alkaloids
• The dried powdered material is extracted completely
for alkaloids, purification, the total mixture of alkaloids
or total volatile alkaloids, or total organic solvent
soluble alkaloids are determined by:
1. Volumetric method
• The alkaloid residue is dissolved in a small amount of
alcohol, treated with known excess volume of acid;
the excess acid is back titrated against alkali as
NaOH.
2. Non aqueous titration
• Non aqueous volumetric titration using glacial acetic
and CHCl3
3. Gravinometric determination :
• It could be used in the following cases:
a. Week alkaloid cannot be titrated as colchicines.
b. Alkaloids occur in a complex mixture varying in
structure formula, molecular weight as in cinchona
alkaloids
4. Colorimetric & spectrophotometric determination :
• Some alkaloids develop colour with special reagent
whose intensity is directly proportional to the concentration
of alkaloids.
Basic nucleus of alkaloids
N
N
H
N
H
Pyrrol
N
Tropolene
Pyrrolizidine
Pyrrolidine
Pyridine
NCH3
N
N
N
H
Piperidine
Quinoline
Isoquinoline
Tropane (Piperidine+Pyrrollidine)
N
N
N
H
N
H
Indole (Benzopyrrole)
Nor-hipinane
N
N
Pyrimidine
Imiidazole
N
N
N
N
N
Purine (Pyrimidine+ imidazole)
N
H
Carboline (Indole+ Pyridine)
Phenantherene
NCH3
NH
N
N
H
Quinuclidine
(Cinchona alkaloids)
Hydroindoline+ Pyrrolidine
N
H
Indole+ Hydroquinoline
(Ergot alkaloids)
(Physostigma alkaloids)
Alkaloidal Classes
Non Heterocyclic alkaloids
Phenyl alkyl amine group
Ephidera alkaloids
a. Occurrence: Ephedrine present in Ephidra sinica & Pseudo-ephedrine
present in Ephidra alata and both are present in E. vulgaris.
a. Preparation of ephedrine:
1. From plant source:
 The powder is alkalinized with Ca(OH)2, macerate with benzene overnight.
 The extract is acidified by Dil HCl, separate the acidified aqueous layer by
separating funnel, make it alkaline with Na2CO3
 Extract with ether, concentrate, Pseudo-ephedrine will crystallize at first then
ephedrine latter.
• N.B. CHCl3 is avoided in Ephedrine extraction otherwise undesirable reaction
Ephedrine + CHCl3
Ephedrine HCl + aldhyde.
2- Fermentation
Fermentation
C6H5-CH(OH)-CO-CH3
Molasses + Benzaldhyde
C6H5-CH(OH)-CH-CH3
Ephidrine
H2+CH3NH2
NH-CH3
3-Chemical Synthesis
Catalytic reduction of phenyl methyl di-ketone in presence of CH3NH2
2H2/P
C6H5-CO-CO-CH3 + NH2-CH3
C6H5-CH(OH)-CH-CH3
NHCH3
Structure
OH
CH-CH-CH3
OH
L-Ephidrine
NHCH3
CH-CH-CH3
NHCH3
d-Pseudo-Ephidrine
Tests for identity:
Ephedrine + 1 ml H2O + Few drops of HCl CuSO4/NaOH reddish
colour, add ether to give two layers (purple upper ether layer&
blue lower aqueous layer
2. Ephedrine + Potassium ferrocyanide H2O/ heat benzaldhyde odour
1.
• Physicochemical Characters:



Natural ephedrine is Levorotatory/alcohol but the aqueous solution
is dextro
Ephedrine base is stem volatile
Ephedrine give negative Mayer's test
Pharmacological activity (Uses):
Ephedrine is widely used in asthma, anti-allergic, bronchodilator, and
nasal decongestant and cough preparations.
Alkaloids of Tropolone group
(Alkaloid amine of Colchicum)
H3CO
H3CO
A
B
A
NHCOCH3
B
NHCOCH3
H3CO
H3CO
OCH3
OR
C
OCH3
C
OCH3
O
Colchicine
O
OCH3
H3CO
H3CO
A
B
A
NHCOCH3
B
NHCOCH3
H3CO
H3CO
OCH3
OR
C
OCH3
C
OH
O
Colcheicine
OH
O
Occurrence: Seeds and flowers of Colchicum automenala
Colchicines possess a tropolene structure (ring C) being non basic as N is involved in amide group, so
it cannot be strictly considered as an alkaloid, however it is referred to it as alkaloid.
Properties:
a. It is soluble in water, week base, neutral to litmus
b. Acid hydrolysis of colchicines with dil HCl
Colchiceine,
add FeCl3, an olive green colour will be formed (This colour is
used to detect Colchiceine in Colchicine).
Test for identity
a. Colchicine + drops of mineral acid give yellow colour
b. Colchicine + drops of Nitric acid give dirty violet colour
Quantitative estimation of Colchicine:
• The green colour developed with Colchiceine serves as a base
for colorimetric method for quantitative estimation of Colchicine
after hydrolysis with acid to give Colchiceine
Uses: Orally or intravenous to relief the pain of Gout
II Heterocyclic Alkaloids
1. Alkaloids of Pyridine and Piperidine group
A. Pyridine containing Alkaloids
a- (Tobacco alkaloids)
Source: The leaves of Nicotiana Tobaccum
N
H
N
CH 3
N
N
Nicotine
N
CH 3
N
Nor-nicotine
Nicoteine
N
H
N
N
N
N
Nicotyrine
N
CH 3
Anabasine
Nicotelline
General properties:
A. Nicotine, nor- nicotine, anabasine are volatile liquid alkaloids
B. Nicoteine, Nicotyrine are non-volatile liquid alkaloids
C. Nicotelline is solid alkaloid.
Nicotine
a. Colourless liquid, have characteristic odour, sharp taste
b. In air become brown rapidly
Test for Identity:
1. Aqueous solution of Nicotine + P. dimethyl amino benzaldhyde,
treated with fuming HCl, rose red colour will be formed.
Uses: nicotine has no medicinal use, but used as insecticide as
nicotine sulphate
Method of assay of Tobacco alkaloids (Colorimetric method):
• Tobacco alkaloids + Cyanogen bromide/Aromatic amine gives
yellow colour, its intensity is measured colourimetry.
• b- Alkaloids having Pyridine nucleus only
•
Trigonelline
•
•
•
1- Methylpyridinium-3-carboxylate
• Source: Foenugreek seeds (and other plants)
• Uses: It is used as a hypoglycemic drug in
diabetic patients
B. Piperidine containing Alkaloids
a- (Lobelia alkaloids)
Source: The herb Lobeline
of lobelia inflate
N
O
OH
CH3
Lobelanine
N
O
O
CH3
Lobelanidine
HO
N
OH
CH3
Test for Identity:
1.Lobeline solution + H2SO4/HCOH
2.Lobeline solution + Froed's reagent
Uses
1.Expectorant, respiratory stimulant, Spasmolytic
2.Treatment of Asthma and bronchitis
3.Stop the habit of smoking
red colour
rose red colour
b- Pomegranate alkaloids
The fruit rind, as well as the root
and stem barks of pomegranate,
Punica granatum , F.Punicaceae
Pelletierine
Isopelletierine
Pseudopelletierine
• Pelletierine tannate is official in the E.P. It is
a mixture of the total alkaloids of
pomegranate bark in the tannate form.
• Uses:
It is used as an anthelmintic for intestinal
parasites mainly tape worms. (The alkaloids
narcotize the tape worms so they lose their
grip to the intestinal wall and are expelled)
2-Tropane Alkaloids
Definition: They are esters of alcoholic base (tropine, scopine, oscine) with
specific organic acids (tropic, atropic acids)
Alcoholic base: Consists of condensation of Pyrrolidine & Piperidone groups:
H
N
H
NH
+
N
H
Piperidine
H
Pyrrolidine
Tropane base
Example of alcoholic bases
H
H
O
NCH3
NCH3
oxy tropane)
6,7-Oxytropine
H
NCH3
OH
OH
Tropine
Alcohol (3-Hydr
HO
OH
HO
Teloidine
Example of acids
O
CH2OH
C
CH
COOH
COOH
Tropic acid
Atropic acid
Major solanaceous alkaloids
Atropine
(ester of tropine & tropic acid)
Source: Hyoscyamus muticus
H
NCH3
O
H
C
C
O
CH2OH
[Racemic mixture of (+) dextro&levo (-): Optically inactive]
Isolation:
Ether/ Conc
The powdered drug is treated with Na2CO3 solution
Ether extract
Na2CO3 solution + acid Aq. layer
PPT.
H2O/ Acetic acid
Filtered, dissolve
in acetone
Crystals of of (+/-)Atropine&
Leave to concentrate
(-)-Hyoscyamine
Test for Identity:
1. Vitalis Test
W.B.heat Yellow residueAlc. KOH
0.1 gm atropine + HNO3
Bright purple colour
Deep red colour
2- Alc. soln. of Atropine+ HgCl
3- Aqueous soln. of alkaloid/HCL + Gold choloride soln.
Lemon yellow PPT
H2O/HCl, Heat
a- Dull PPT (Atropine)
b- Lusterousgold yellow leaflets (Hyoscyamine)
c- Lusterous yellow prisms (Scopolamine)
B. Hyoscyamine (Levo form of (-)-Atropine)
C. Scopolamine = Hyoscine
Source: Hyoscyamus niger
O
NCH3
H
O
H
C
C
O
CH2OH
(ester of 6,7-Oxytropine & tropic acid)
Uses of tropane alkaloids: Antispasmodic, Dialate eye pupil, Sedative
effect
2-QuinolineAlkaloids
Cinchona alkaloids
Source: Cinchona bark Fam. Rubiaceae
The important Cinchona alkaloids are 2 pairs of sterioisomers,
Quinine (levo), Quinidine (dextro) and Cinchonine (d),
Cinchonidine (l).The Cinchona alkaloids are present in the plant
in combination with special organic acid as Quinic acid.
HO
CH2=CH2
COOH
OH
Quinic acid
H
C
N
HO
OH
R
OH
N
Quinine (β OH), Quinidine (α OH) R= OCH3
Cinchonine (β OH), Cinchonidine (α OH) R= H
Quinine
It is diacidic base so forms with H2SO4, bisulphate salt
which is water soluble
Test for identity:
1. Quinine + oxygenated acids (H2SO4 or HOAc), a blue
fluorescence is formed
2. Thalloquine Test:
Quinine salt + drops Br2/H2O + Conc. Ammonia,
green colour
3. Resequine Test
Quinine + dil HOAc + Br2/H2O + K Ferrocyanide + one
drop Conc. Ammonia, give red solution + 1 ml CHCl3,
Shake, the colour is taken by CHCl3
Quinidine
Test for identity: Ferrocyanide Test:
Heat, W.B.
Quinidine salt + 5 ml/H2O
+ 1ml CHCl3
drops of Ferrocyanide +
3 ml NaOH, Shake
CHCl3 layer become red
but in case of Quinine salt
the CHCl3 layer still colurless
Uses
•Quinine used as antimalarial drug
•Quinidine used as antiarrhythmic drug in auricular
fibrillation.
3-IsoquinolineAlkaloids
This group of alkaloids is of 2 types:
a-Curare alkaloids
b- Opium alkaloids
a. Curare Alkaloids
Source: bark and stem of Chondodendron
tomentosum
H3CO
CH3
N+
CH3
HO
The only active alkaloid is d- Tubocurarine
It contains 2 molecules of P-OH benzyltetrahydro
isoquinoline
It has quaternary N so the base is H2O/soluble.
CH2
O
H2C
OH
O
H3C
+N
H3C
OCH3
d- Tubocurarine
Test for Identity:
Aqueous solution of d- Tubocurarine + HCl+ Na2 CO3,
gives yellow brown PPT
Uses:
1. Skeletal muscle relaxant in surgical operation
2. Anticonvulsant
3. Diagnostic agent in myasthenia gravis
b-Opium alkaloids
Source: Latex extract obtained after incision of unripe fruit of Papaver sominife
rum F. Papaveraceae
Opium alkaloid contains several classes:
Benzyl isoquinoline (Papaverine, Narcotine)
Phenanthrene (Morphine, Thebaine, Codeine).
The opium alkaloids present in the form of salt with Meconic acid which is
O
dibasic acid.
OH
HOOC
O
COOH
Meconic acid
Detection of Meconic acid:
Solution of meconic acid or its salt as meconate of opium alkaloids
+ FeCl3, gives deep purplish red colour
Benzyl isoquinoline opium alkaloids
Papaverine
Test for Identity:
1- Papaverine + HCl, heat, red colour,
On excessive heating the red colour
Disappear
2- 5 ml of Papaverine + 5 drops of potas
sium ferricyanide T.S. a lemmon
yellow ppt is produced of Papaverine
ferricyanide
Uses: Smooth muscle relaxant (Antispa
smodic)
H3CO
N
H3CO
CH2
H3CO
H3CO
Papaverine
Phenanthrene group of opium alkaloids
(Morphine type of alkaloids)
Morphine
H3C
N
HO
O
OH
Morphine
Morphine is monoacidic base. It dissolves in alkali, Ca(OH)2.
Morphine
Morphine
(Methylation of phenolic OH)
Diazomethane
(Acetylation)
Acetic unhidride
Heroin
Codeine (Methyl
morphine)
Test for Identity:
1- Iodic acid test:
Morphine + H2SO4 + IO3 (Iodic acid)
Violet colour in CHCl3 layer
Disappearance of the
yellow colour of iodic
acid
CHCl
3
2- Nitrous acid test
Morphine HCl + NaNO2 + NH4OH
red colour
C.F. Codeine gives
blue colour
N.B. This colour is used for colourimetric assay of morphine
H3C
2-Codeine
N
H3CO
O
OH
Codeine
The codeine is soluble in H2O and CHCl3 while morphine is insoluble in H2O and CHCl3
Test for Identity: as under morphine
3-Thebeine
H3C
N
H3CO
O
OCH 3
It is dimethoxy derivative of morphine. It has no phenolic or
alcoholic OH so don’t dissolve in alkali
red blood colour
Test for Identity:; Thebeine + H SO
2
4
orange yellow
How to separate mixture of morphine, codeine and thebaine?
The alkaoid mixture
NaOH
Aqueous sol: morphine + codeine as phenates
CHCl3
Codeine in CHCl3 layer
PPT of thebeine
morphine in aqueous layer
Uses:
•Morphine is hypnotic and narcotic (CNS depressant)
•Codeine is analgesic, antitussive and sedative
Indole group of alkaloids
I-Alkaloids of Physostigma (Calbar beans)
II-Alkaloids of carboline group (Rauwolfia)
III- Ergot alkaloids
IV-Vinca alkaloids (Anticancer alkaloids)
Calbar beans Alkaloids
Source: Seeds of Physostigma venenosum
The major alkaloids are Eserine& Eseroline
O
H3C
HN
C
HO
O
H3C
H3C
N
N
N
N
Eserine (Physostgmine)
Eserine
CH3
CH3
CH3
Eseroline
Alkali Hydrolysis Eseroline + CO + CH -NH
2
3
2
NaOH
CH3
Tests for Identity
1- Physostgmine + NH4OH
2- Physostgmine + KOH
Heat on W.B.
Yellow red
Heat on W.B.
Blue
residue
Deep yellow colour
Uses: Physostigmine is used topically as miotic in Eye
oint.
1. Alkaloids of carboline group (Rauwolfia Alkaloids)
Source: Roots of Rauwolfia serpintina
Groups of Rauwolfia alkaloids:
1. Colourless week bases of tertiary indole alkaloids as reserpine
2. Yellow coloured strong quaternary bases as serpentine
N
R
Reserpine R= OCH3
Deserpidine R= H
OCH3
N
H
O
H3CO
C
C
OCH3
O
OCH3
OCH3
O
N
H3CO
OCH3
H
C
N
H
O
Resinnamine
H3CO
C
O
C
O
OCH3
OCH
C
H
3
OCH3
Reserpine is methyl ester of pentacyclic reserpic acid linked by an ester linkage to trimethoxy benzoic
acid
Reserpine, on alkali hydrolysis (NaOH) gives resepic acid + MeOH + trimethoxy benzoic acid
Resinnamine is methyl reserpate linked by ester linkage to trimethoxy cinnamic acid
Isolation of Rauwolfia alkaloids:
Powder root of R.S
Moist with 10% NaCO3
Extract with benzene
Benzene extract
Concentrate, add HCl
Acidic aq. layer
Extract with CHCL3
CHCl3 Layer
Add Na2CO3, evaporate
Residue
Dissove in Alcohol, concentrate
Reserpine
Aq. layer
Evaporate,
dissolve in
benzene
Resinnamine
+ deserpidine
Quantitave estimation of reserpine: By non-aqueous determination
Uses:
•Antihypertension
•Sedative
•Tranquilizer
III- Ergot alkaloids (Ergolines)
Natural source:
 Ergot is the dried
sclerotium of the fungus
Claviceps purpurea Family
Hypocreacea that arise
on the ovaries of the rye
plant (Secale cereale, Family
Graminae)
•
Ergot alkaloids are N-monosubstituted amide derivative of both
Lysergic acid and its isomer Isolysergic acid.
•
Members related to Lysergic acid e.g. Ergotamine and Ergometrine
are levorotatory, these are the pharmacologically active
members and designated by suffix “ine
Members related to Isolysergic acid ending with the suffix inine
and are dextrorotatory e.g. Ergotaminine and Ergometrinine
these are pharmacologically inactive.
1- Simple lysergic acid amides
• Ergonovine (Ergometrine)
•
1- They are water soluble
2- On hydrolysis gives 2-amino propanol and lysergic acid
3- Aqueous solution of ergot alkaloids on long time and exposure to
UV changed to lumi alkaloid (inactive alkaloid) where saturation of
∆9=10
Uses:
1- Ergometrine is used as an Oxytocic, and is injected during the final
stages of labour and immediately following child birth, especially
if hemorrhage occurs.
2- Bleeding is reduced because of its vasoconstrictor effects, and it is
valuable after Caesarian operations.
Detection of Ergot alkaloids:
Keller's test
• Ergot Alkaloid in glacial acetic acid + trace FeCl3 + Conc. H2SO4
gives blue colour at junction of the two layers
Vanurk test (P.dimethylaminobenzaldhyde + 5% FeCl3 + H2SO4)
 Ergot alkaloid + Vanurk reagent gives deep blue colour
 This reagent could be used for Quantitave determin-ation and as sp
ray reagent for their detection on TLC.
2. The Polypeptide Alkaloids
• Ergotamine
•
1- They are insoluble in water
2- On Hydrolysis gives d-proline, phenyl alanine,
hydroxyalanine and lysergic acid
Ergotamine
Proline
H
HO
O
Hydroxy alanine
N
O
N
H3C
HN
O
O
Phenyl alanine
CH3
N
H
Lysergic acid
N
H
Hydroletic products of Ergotamine:
OH
HO
O
O
CH3
N
H
H2N
Lysergic acid
Phenyl alanine
N
H
HO
OH
Proline
H3C
H2N
O
H
NH
HO
O
Uses:
1- Ergotamine is used in the treatment of acute attacks of migraine,
2- Ergotamine is effective orally, or by inhalation in aerosol form, and
may be combined with caffeine for treatment of migraine.
Ergotism
• It is a poisonous case resulting from the chronic consumption
of rye or wheat flour contaminated with ergot. Alkaloids of ergot
cause vasoconstriction especially in the limbs that may results by
time in gangrene of one or more limbs.
•
IV- Vinca Alkaloids (Anticancer alkaloids)
Source: The dried whole plant of Catharanthus
roseus (Family Apocyanaceae)
• More than 90 different alkaloids have been
isolated; the most important are vincristine and
vinblastine
They are complex bis-indole (dimeric alkaloids)
Indole and dihydro indole nuclei i.e. they are
dihdro- indole alkaloids and used as sulphate
Action and therapeutic uses:
• Vincristine: It is most effective in treating
childhood leukemia and non-Hodgkin's
lymphomas.
• Vinblastin: It is used to treat Hodgkin's
disease (a painless localized enlargement
of lymph nodes in one side of the neck.
Symptoms are fever, itching and eruption
of the skin)
Imidazole Alkaloids
Pilocarpine
Source; Leaves of Pilocarpus Japorandi
CH3
C2H5
N
Pilocarpine
O
O
N
It is tertiary base, oily liquid, contain lactone group
Pilocarpine on heating with HCl, demethylatin to give Pilocarpdine.
Isolation:
Powder leaf is extracted with Alcohol/HCl
Pilocarpine
Nitrate PPT
HNO3
CHCl3 extract, concentrated
Acidic alcoholic
extract
1- NH4OH, 2- CHCl3
Test for identity:
1- Helches' Test
Pilocarpine + H2SO4 + K2Cr2O7 + HCl + HCl
Violet colour
2- Ekkeret's Test
Pilocarpine + Na nitroprosside + NaOH Leave for a period, Hcl
Wine red colour
3- Mandalene test: Pilocarpine solution + Mandaline R.
(sulphovanidic acid) gives yellow colour which on heating becomes
green then blue after further heating.
Uses:
Treatment of glaucoma (myotic action).
Purine Bases or Xanthine Bases
The purines are derivatives of hetrocyclic nucleus, consists of fused Pyrimidine & Imidazole rings.
The purine does not occur in nature but the pharmacologically important bases are Xanthine bases =
2,6-dioxy purine
- Caffeine (1,3,7 Trimethyl xanthine)
- Theophilline (1,3 dimethyl xanthine)
- Theobromine (3,7 dimethyl xanthine)
NH
N
N
N
Imidazole
Pyrimidine
R
Caffeine
Theophylline
Theobromine
CH3
CH3
H
O
H
N
N
H
N
HN
N
N
Purine
O
N
H
N
Xanthine
O
R'
CH3
CH3
CH3
R"
CH3
R
N
N
H
O
CH3
N
R'
Enolization only occur in Theobromine
O
H
O
OH
CH3
N
N
N
CH3
N
Keto form
O
CH3
N
N
N
R"
N
CH3 Enol form
N
• General characters of Xanthines:
1. They combine with organic acids e.g. citric acid or salts of
organic acids as NaOAc which increases their solubility in water.
Caffeine citrate is 12 times as soluble as Caffeine in water.
2. They don’t give PPT with Mayer's Reagent but gives brown PPT
with Wagner's reagent.
3. They are very week base, only form salts with strong acids which
are easily hydrolyzed in water giving base which can be extracted
with immiscible organic solvents.
4. By toutomeric shift, enolization only occurs in Theobromine so
can dissolve in strong alkali forming salts.
5. As a positive test for identity for all alkaloids of this group
(Muroxide test):
Heat untill dryness
Little of xanthine alkaloid + HCl + KClO3
Decolourization NaOH Purple colour
Residue
Ammonia vapour
1. Caffeine
Source: Seeds of Coffee Arabica
Isolation
A. From Plant source: The powder tea leaves are refluxed with water, filter, the
filtrate is treated with PbOAc to PPT the tannin, filter, The excess Pb (Lead) is
removed by adding Na2HPO4, filter, concentrate, extract with CHCl3, evaporate
, the residue is boiled with water, set aside, caffeine crystals will deposited.
B. Partial synthesis:
O
+Ag
O
N+
CH3
OH
H3C
N
N
N
+ AgI
+ CH3I
N
N
Ag salt of
CH3 Theobromine
O
CH3
N
CH3
N
Caffeine
Test for Identity: Muroxide test
Uses: CNS stimulant causing increase of thought, decrease the
drowness and fatigue, relieves the headache and give the sense of
comfort.
2- Theobromine (3,7 dimethyl xanthine)
O
H
N
N
O
CH3
N
N
CH3
Theobromine
Source: Seeds of Theobrima Coca
Properties:
•It is not very soluble in H2O (1:800) but becomes readily soluble in H2O if it is
mixed with salts which forms basic solution as Ca salycilate or NaOAc.
•It shows amphoteric characters as a week acid or week base so it is soluble in
strong alkali (NaOH) or strong acid (HCl)
•It forms definite insoluble salt with AgNO3
Solution of Theobromine/NH4OH
AgNO3
Ag. salt PPT
Just the same case as theophilline while caffeine cannot.
Uses: Diuretic in case of oedema
3-Theophilline (1, 3 dimethyl xanthine)
O
H3C
N
N
O
H
N
N
CH3
Source: Tea leaves (Camellia sinensis)
Theophylline
Properties:
1. It is soluble in H2O (1:1200) but freely soluble in alkali hydroxide and
ammonia
1. It forms salt with AgNO3 to give Ag Theophilline which serves as method for
separation of Theophilline from Tea leaves and could be liberated from the
Ag salt by passing H2S
Uses: Smooth muscle relaxant, myocardial stimulant and diuretic.
Separation of mixture of caffeine, theobromine and theophilline:
Caffeine is extracted from the mixture with benzene. The remaining 2 alkaloids are
treated with NH4OH which dissolves theoplillline leaving theobromine insoluble
Indolizidine alkaloids
OH
OH
H
OH
H
OH
HO
HO
N
N
HO
HO
Castanospermine
6-Epi-Castanospermine
Source: seeds of castanospermum australe
Isolation from plant source:
a- The powdered drug is pretreated with alkali to liberate the
free alkaloid base, extracted with ether or CHCl3
b- The CHCl3 extract is evaporated under vacuum to afford the
total alkaloid extract.
Uses: Anti HIV (Anti AID)
N.B. The O-acetyl derivative show activity 20 times as anti HIV than
parent compound
Steroidal alkaloids
Solanum alkaloids (Solanine alkaloid)
CH3
CH3
CH3
N
CH3
RH-Gal-Gluc-O
It is glyco-Alkaloid
Source: Solanum niger
Isolation:
• The powder is extracted with alcohol containing 1%
acetic acid
• The alcoholic extract is concentrated, extracted
with acetic , the acetic acid solution is rendered
alkaline by NH4OH to precipitate solanine, filtered.
Test: Solanine + H2SO4 + HCOH give red violet colour