Lecture №23
Alkaloids as medicines. Sources of
obtaining, methods of the structure
determination. Their chemical
classification, general methods of
qualitative and quantitative
determination. Alkaloids, imidazole’s,
pyrolysidine’s, quinolysi(di)ne’s,
quinoline’s derivatives, with exocyclic
nitrogen atom.
ass. Medvid I.I.
Definition of alkaloids:
Alkaloids – nitrogen containing organic bases,
usually of plant origin, which have an active
biological action.
Alkaloids are similar to alkali.
Alkaloids - complex derivatives of ammonia,
which have replaced hydrogen atom on
radicals: tertiary or secondary amines, or
derivatives of four substituted ammonium
bases.
Alkaloids are weak bases. Codeine has the
strongest basic properties (К= 9·10-7), caffeine
– the weakest (К = 4,1·10-14).
Distribution in nature:
Alkaloids, related by structure, often can be found
in plants that are close in botanical terms. Mainly in
one plant is a mixture of alkaloids (exception –
castor plant containing ricynine). Some plants
(cinchona, poppy seeds, barberry) containing up to
10-15% of alkaloids.
Localization - most aerial parts of medicinal plants
(flowers, fruits, leaves, cortex). Some alkaloids can
be moved from one part of plant to another part.
Their content in plants depends on the: climate,
temperature, altitude above the sea level and
others. So the content of ephedrine in Ephedra
may change during the year from 0.3% to 2,5%.
Historic moments of alkaloid
chemistry research:
In 1804 the French pharmacist Sehen allocated
morphine from opium as a technical product.
In 1816 professor of the Kharkiv University
F.I. Giza allocated quinine. In 1818 year were
discovered strychnine and brucine, and a year
later - caffeine.
y. А.А. Voskresenskiy opened
theobromine, and in 1847 J.F. – Fritzsche hormyn.
In
1842
A.M. Butlerov and A.N. Vishegradskiy on the
basis of their experimental work concluded that
all alkaloids are derivatives of pyridine and
quinoline.
In 1881 y. in Russia first synthesis of coniine was
conducted.
1915 y. – Chychybabin with Rodionov began
industrial production of opium and other alkaloids.
In 1917 y. first alkaloid plant began work in Russia.
Important role in the development of chemistry
played A.P. Orekhov and his school. They
investigated 1500 species of plants, found more
than 250 alkaloid containing plants, issued
monograph "Chemistry of alkaloids”.
N.А. Preobrazenskiy in 1933 at first made the
original synthesis of pilocarpine.
Classification of alkaloids
Alkaloids are naturally occurring chemical compounds containing basic nitrogen
atoms. The name derives from the word alkaline and was used to describe any
nitrogen-containing base. Alkaloids are produced by a large variety of
organisms, including bacteria, fungi, plants, and animals and are part of the
group of natural products (also called secondary metabolites). Many alkaloids
can be purified from crude extracts by acid-base extraction. Many alkaloids are
toxic to other organisms. They often have pharmacological effects and use as
medications and recreational drugs. Examples are the local anesthetic and
stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or
the antimalarial drug quinine. Some alkaloids have a bitter taste. Alkaloids are
usually classified by their common molecular precursors, based on the
metabolic pathway used to construct the molecule. When not much was known
about the biosynthesis of alkaloids, they were grouped under the names of
known compounds, even some non-nitrogenous ones (since those molecules'
structures appear in the finished product; the opium alkaloids are sometimes
called "phenanthrenes", for example), or by the plants or animals they were
isolated from. When more is learned about a certain alkaloid, the grouping is
changed to reflect the new knowledge, usually taking the name of a
biologically-important amine that stands out in the synthesis process.
Types of the alkaloid classifications
•
By the chemical structure:
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
derivatives of pyrrolidine (sthrahidrine, turicine)
derivatives of tropane (atropine, cocaine)
derivatives of pyperidine (lobeline, coniine)
derivatives of pyridine (nicotine, anabasine)
derivatives of pyrrolysidine (platyphylline)
derivatives of quinolysidine (pahicarpine, lupinine)
derivatives of quinoline (quinine)
derivatives of isoquinoline (papaverine, morphine)
derivatives of indol (reserpine, strychnine)
derivatives of purine (caffeine, theobromine,
theophylline)
11) derivatives of the different heterocycles
(imidazol (pilocarpine), thiazol (agroheline),
quinazoline (luotoline А), acridine
(rutacridone), azenine (galantamine));
12) polypeptide alkaloids (13-, 14-, і 15-member)
(buckthorn alkaloids);
13) alkaloids with exocyclic nitrogen atom
(ephedrine, muscarine, spherophysine);
14) terpenoid alkaloids (acronicyne, actinidine);
15) steroid alkaloids (solasodine, cholophyllamine).
• By the ways of their biosynthesis
(according to the substances from which they are
obtained):
a) true alkaloids (1-12 group) – which is synthezed
from aminoacids and heterocycles are the base of
their structure;
b) protoalkaloids (13 group) – do not include
heterocycles, also are the plant amines and
formed from aminoacids;
c) pseudoalkaloids (14, 15 group) – obtained by
others ways different from aminoacids.
• By plant sources
Classification of alkaloids by
Orekhov
• Acyclic and alcaloids with exocyclic nitrogen
atom (ephedrine hydrochloride,
sphaerophysine benzoate, colchamine,
colchicine)
• Derivatives of pyrrolidine and pyrrolysidine
(platyphylline hydrotartrate):
N
N
H
•
Derivatives of pyridine (nicotine) and
piperidine (lobeline, coniine):
N
N
H
• Condensed pyrrolidine with piperidine (tropane):
N CH 3
•
Derivatives of quinolysine (cytisine) and
quinolysidine (pachycarpine hydroiodide):
N
N
• Derivatives of quinoline (salts of
quinine) and isoquinoline (papaverine
hydrochloride, opium alkaloids):
N
N
•
Derivatives of indol (physostigmine salicilat,
strychnine nitrate, reserpine):
N
•
H
Derivatives of quinazoline:
N
N
•
Derivatives of imidazol (pilocarpine
hydrochloride):
N
N
H
• Derivatives of purine (caffeine, theophylline,
theobromine):
N
N
H
N
N
•
•
Diterpene alkaloids (aconite, isoprenoide).
Steroid alkaloids and glycoalkaloids:
Nowadays, it is known more than 5000 different
alkaloids, while for 3000 of them installed
molecular structure.
Methods of extraction from plant materials
extraction in the form of salts (water,
alcohol, tartaric acid);
extraction in the form of basis (NH4OH,
NaHCO3);
Distillation of alkaloids bases with
aqueous steam (boiling point for which is
less than 100 º C).
Extraction as salts: to raw material add water or
ethanol with few drops of tartaric acid. All alkaloids
forms salts with tartaric acid. For purification to this
extract add base and all alkaloids form bases, which
obtained by organic solutions. Operation of
purification repeat few times. Then solvent
separated from alkaloids. Sum of alkaloids is
separated on individual compounds.
Extraction as bases: to raw material add alkali
solution (ammonium, sodium hydrocarbonate or
carbonate). Alkaloids bases are extracted by organic
solutions. Purification realize by transferring
alkaloids to salts and then to bases. Operation of
purification repeat few times.
The methods of separation of the
selected amount of alkaloids:
Fractional distillation in vacuum;
By the different solubility of alkaloids –
salts and bases;
By the different power of basic properties of
alkaloids;
based on the features of chemical properties;
By the different ability to adsorption
(chromatography);
Method of anticurrent separation.
For identification of alkaloids use general,
group and specific reaction.
The general reactions conduct with common
alkaloid precipitation and special reagents.
General precipitate reactions based on the
ability of alkaloids as bases to give simple or
complex salt with different, more often
complex acids, salts of heavy metals and
others. These products are usually not soluble
in water, so called precipitate.
General alkaloid precipitate reagents:
Dragendorph reagent – BiI3+KI↔K[BiI4] SPU
Lyugol, Vagner, Bushard reagents– sol. І2 in
КІ in different concentraions
Maier reagent – HgI2 + 2KI↔K2[HgI4]
Marme reagent (solution CdI2 в KI)
Zonnenshten reagent - Н3Р04 • 12Мо03 • 2Н20
Sheibler reagent - Н3Р04 • 12WоО3 • 2Н20
Berthran reagent - SiO2 • 12Wо03 • 4Н20
5% Tannin solution (freshly prepared).
Saturated solution of picric acid.
Special (painted) reagents on alkaloids:








Conc. H2SO4.
Conc. HNO3.
Erdman reagent (H2SO4 conc.+HNO3 conc.).
Phrede reagent ((NH4)2MoO4+H2SO4 conc.).
Marki reagent (HCOH+H2SO4 conc.).
Mandelin reagent (NH4VO3+H2SO4 conc.).
Sodium nitroprusside (Na2[Fe(CN5)No]·2H2O).
Vazitsky reagent (solution of pdimethylaminobenzaldehyde in conc. H2SO4).
Methods of the quantitative
determination of alkaloids:
Acid-base titration in nonaqueous environment – for the
quantitative determination of both salts and bases.
Acid-base titration:
а) acid-base titration, direct titration of acids and bases;
b) acid-base back-titration for determination of bases by reverse
titration;
c) Alkalimetry – titration of alkaloids salts by alkali in water-alcohol
medium in the presence of phenolphthalein (with or without
the usage of organic solvent that does not move with water
for extraction of alkaloid bases)
d) Alkalimetry by the substituent
Gravimetric method
Methods based on individual chemical properties of alkaloids.
Physico-chemical methods.
Alkaloids with exocyclic nitrogen
atom
Ephedrine hydrochloride
(Ephedrini hydrochloridum)
H
C
H
C
CH3
HCl
OH NHCH3
(-) 1-Phenyl-2-methylaminopropanol-1 hydrochloride
Sphaerophysine benzoate
(Sphaerophysini benzoas)
H3C
NH
CH
H3C
C
H
C
H
N
H
C
H2
C
H2
C
H2
C
H2
N
C
2 C6H5COOH
H
NH2
1-guanidino-4-(isoamylene-11)-aminobutane
dibenzoate
Ephedrine contains in different
types of Ephedra, together with its
stereoisomers
L-ephedrine (cysisomer, left-rotation)
C6H5
H
H
C
C
CH3
OH HN
CH3
D-pseudoephedrine
(trans-isomer, rightrotation)
OH H
C6H5
C
C
CH3
H HN
CH3
Ephedra monosperma
Obtaining of ephedrine by synthetic
method
Benzene with chloroanhydride of chloropropanoic acid is
condensed at the presence of AlCl3 (Fridel-Crafts reaction).
Obtained chloroethylphenylketone condensed with
methylamine, aminoketone is formed which is reduced to
ephedrine:
O
H
C
H 3C
C
Cl
Cl
C6H6
C6H5
C6H5
-HCl
(H)
C
H
C
O
NHCH3
CH3
C6H5
C
H
C
O
Cl
H
C
H
C
CH3NH2
CH3
CH3
OH NHCH3
-HCl
Sphaerophysa salsula
Physical properties
Ephedrine hydrochloride
Colorless needle crystals or
white crystalline powder,
odorless, with bitter taste.
Easily soluble in water (so
under the action of alkali
precipitate is not falls - the
difference from other
alkaloids), soluble in alcohol,
practically insoluble in ether.
Sphaerophysine
benzoate
White crystalline
powder with bitter
taste. Soluble in
water, alcohol, alkalis,
insoluble in ether and
chloroform.
Identification
Ephedrine hydrochloride
Sphaerophysine
benzoate
1. Reactions on chlorides
2. With CuSO4 at the presence of 1. With HCl – white
precipitate of benzoic acid
NaOH – blue complex
falls.
compound (At the shaking of
this solution with ether, ether 2. At the boiling with alkalis
layer paints in red-violet
urea separated and then NH3
color, water layer keeps blue 3. With sodium nitroprusside
color).
alkali solution, later HCl –
3. At the heating with potassium
cherry-red color which
ferrocyanide crystal smell of
quickly disappears.
benzaldehyde appears (bitter
almond).
4. Specific rotation: from -33° to
-36° (5 % water solution).
Quantitative determination
Ephedrine hydrochloride
Sphaerophysine
benzoate
Acidimetric titration in
nonaqueous medium in the
1) Acidimetric titration in
presence of mercury (II) acetate
nonaqueous medium in the
(indicator crystal violet,
presence of ice acetic acid
Е=М.m).
(indicator crystal violet,
Е=М.m/2).
2) Alkalimetric titration alcoholchloroform medium (Е=М.m). 2) Bromatometry, direct
titration (Е=М.m/2).
3) Argentometry by the linked HCl
(Fajans’ method with the usage
of bromothymol blue indicator)
(Е=М.m).
1)
Storage, application
Ephedrine hydrochloride
Sphaerophysine benzoate
Drastic compound. In
tightly closed container (TCC)
which keeps from the action of
light.
Sympathomimetic
(vasoconstrictive,
bronchodilating) mean. By the
action it is close to adrenaline,
has specific stimulatory action
on CNS. Internally by 0,0250,05g 2-3 times per day, i/m or
i/v (intravenous) by 1 ml of 5%
solution. Included to the content
of Theophedrine tablets,
Ephatine aerosol, Solutan and
Broncholitine syrups.
Drastic compound. In orange
glass tightly closed container, in
the place protected from lightв.
Ganglioblockator mean,
uterine muscle stimulant. Used
for the treatment of
hypertension and strengthening
of maternity activity by 0,03g 23 times per day or i/m by 1ml of
1% solution.
Colchamine and colchicine – alkaloids from
different types of Colchicum, toxic compounds,
use as ointments in the treatment of skin
cancer
• Colchamine
• Colchicum autumnale
Alkaloids – derivatives of imidazol
Pilocarpine hydrochloride (Pilocarpini
hydrochloridum)
C2H5
C
H2
O
O
N
CH3
HCl
N
α-Ethyl-β-(1-methylimidazollyl-5-methyl)γ-butyrolactone hydrochloride
(3S,4R)-3-Ethyl-4-[1-methyl-1Н-imidazol-5-yl)methyl]dihydro-3Нfuran-2-one hydrochloride
5(3-ethyl-4,5-dihydrofuranone-2)-methylene-1-methylimidazol
hydrochloride
Obtaining of pilocarpine
Pilocarpus Jaborandi
Was obtained in 1875
y. Diminished in size dry
leaves extracted by
acidified alcohol. Distilled
alcohol from the extract
and separated free
alkaloids which transfer
to nitrates and then to
hydrochlorides. Alkaloids
are separated by the
factional crystallization
or chromatographic
method.
Pilocarpine was synthezed in 1933 y. by А.M. Preobrazenskiy
from homopilopic acid, which obtained from diethyl ether of
ethylamber acid С2Н5СН(СООС2Н5)СН2СООС2Н5 by the
following scheme:
Physical properties of pilocarpine
hydrochloride
Optical active, has two asymmetric carbon atoms. Colorless
crystals or white crystalline powder, odorless. Hygroscopic. It is
easily soluble in water, easily soluble in alcohol, practically
insoluble in ether and chloroform.
Identification of pilocarpine hydrochloride
1.
2.
3.
Substance gives reaction on chlorides.
Chelch sample. Reaction of the formation of above chromic
acids (mixture Н2О2, Н2SО4 conc., К2Сr2О7) and
chromoperoxide (CrO5), which with pilocarpine base forms
blue-violet complex compound soluble in chloroform. At the
absence of pilocarpine colored product is not extracted by
chloroform.
Legal reaction on lactone ring. With sodium nitroprusside in
alkali medium – cherry-red color, which does not disappear
when you add excess of chloride acid. This reaction can be used
for the photocoloeimetric determination of pilocarpine in 1 %
water solutions.
4. Specific rotation from +88,5° to +91,0° (2 % water solution).
5. Hydroxame reaction (presence of the lactone ring – butyrolactone):
6. Preparation at the grinding with calomel becomes black as a result
of formation of metallic mercury at the pilocarpine oxidation:
Pilocarpine  Pilopic acid+ Methylurea
Quantitative determination of
pilocarpine hydrochloride
1. Acid-base titration in nonaqueous medium in the
presence of mercury (II) acetate (Е=М.m).
2. Alkalimetry in alcohol medium (Е=М.m).
3. Iodometry, reverse titration (after the separation of
polyiodide precipitate).
Storage
Poison compound. In tightly closed container, which
keeps from the light and moisture.
Application
Cholinolytic (myotic) mean. Prescribed as eye
drops (1-2% solution) or ointment for the treatment of
glaucoma.
Alkaloids – derivatives of
pyrrolysidine
Platyphylline hydrotartrate
(Platyphyllini hydrotartras)
CH3 CH3
H3C
C
H
C
C
C
H2
O
C
H
O
C
OH
C
O
O
CH2
N
HO
HOOC
H
C
C
H
COOH
OH
To establish the structural formula of platyphylline you
should study the products of its hydrolysis. At the
heating with alcoholic solution of alkali platyphylline
decomposes on aminoalcohol platynecyne and
synecionilic acid:
So, platyphylline – cyclical diester, in which two
hydroxyl groups of platynecyne are etherificated by
synecionilic acid.
Senecio plathyphylus
Platyphylline and his
companion seneciphylline are
derivatives of 1-
methylpyrolysidine, was
extracted in 1935 y. by О.
P. Orekhov і R. А.
Conovalova from the roots
and herb of Senecio
plathyphylus.
Properties of platyphylline hydrotartrate
A white odorless crystalline powder with weak or
specific smell and bitter taste. Easily soluble in water,
very little soluble in alcohol, practically insoluble in
chloroform and ether.
Identification of platyphylline hydrotartrate
1. Speciofic rotation from -38° to -40° (5 % water
solution).
2. With Dragendorph reagent forms orange precipitate.
3. With Mayer reagent forms white precipitate.
4. Formation of iron (III) hydroxamate red color (ester
group).
5. Substance gives reaction on tartrates:
a) with potassium salts – white crystal precipitate;
b) with 0,1 М AgNO3 solution – white precipitate. To the one
part of solution add dil. НNO3 – precipitated dissolves; at the
heating of second part of precipitate with NH4OH on the
walls of the tube forms silver mirror”, cases by the properties
of tartaric acid;
c) with β-naphthalene in the presence of Н2SО4 conc. Green color
appears at heating; if instead β-naphthalene used resorcinol –
red-violet color of aurine dye-stuff :
HO
H
OH
+
HO
OH
C
H2SO4
CH
+
-2H2O
OH
OH
O
OH
HO
H2SO4
C
-2H2O
OH
O
Aurine dye-stuff
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Quantitative determination of platyphylline
hydrotartrate
1. Acid-base titration in nonaqueous medium, a direct
titration, the indicator - crystal violet (Е=М.m).
2. Alkalimetry in alcohol-chloroform medium (Е=М.m).
3. Iodometry, back-titration (by the reaction of formation of
polyiodide in saturated solution of NaCl).
4. Photocolorimetry – on the basis of the reactions with
general alkaloid color reagents.
5. Extraction-photometric – determination of platyphylline
hydrotartrate in the injection solution and tablets by the
reaction with tropeoline 000-ІІ.
6. UV- spectrophotometry, GLCH.
Purity test
Seneciphylline - unacceptable impurity: there should be no
distraction while adding of 5% ammonia solution.
Storage
Poison compound. In tightly closed container. In dry place.
Application
m-Cholinolytic (spasmolytic, midriatic) mean. At the
spasms of smooth muscles of the abdominal cavity,
spasms of blood vessels, bronchial asthma and others.
Highest one-time dose. - 0,01 g, highest daily dose - 0,03
g. Subcutaneous (s/c) 0,2% 1,0 ml, eye drops -1%.
Alkaloids – derivatives of
quinolysine
Cytisine (Cytisinum)
NH
N
O
Derivative of 1,2,3,4 tetrahydroquinolysine-6,
condensed with piperidine
White or slightly yellowish crystalline powder. Easily
soluble in water, alcohol and chloroform.
Cytisine is extracted from seeds by 60% alcohol acidified by
acetate acid. Extract is evaporated to the dry state, added to the
alkali residue and extract alkaloids by chloroform. Chloroform
extract evaporated to the dry state and separated alkaloids by
factional crystallization or usage of the ion-exchange resins.
Substance is purified by the distillation in vacuum.
Cytisus laburnum
Thermopsis (Thermopsis
lanceolata)
Identification of cytisine
1. By the physico-chemical constants: melting point,
specific rotation.
2. Nitration reaction of the aromatic ring with
subsequent reduction of the nitro-group to the
amino-group and azodye formation.
3. With solution of cobalt (II) nitrate - blue-green
sediment.
4. With solution of iron (III) chloride - red color,
which disappears when you add water.
5. The reaction of alkaloids with Dragendorph
reagent.
O2N
NH
HNO3
NH
N
[H]
N
O
N
H2N
NH
N+
O
NaNO2
NH
HCl
N
Cl-
N
O
O
O
N
HO
N
NaO
NaOH
N
NH
Quantitative determination of cytisine
Acid-base titration in aqueous medium, a direct
titration, the indicator - methyl red (Е=М.m).
Nitrogen atom in piperidine cycle is titrated.
Storage
Poison compound. Protect from moisture.
Application
Stimulant of blood circulation and respiration.
From cytisine produced 0,15 % water solution of
cytitone for injections. Cytisine is a part of the
tablets against smoking “Tabex”.
Alkaloids – derivatives of
quinolysidine
Pachycarpine hydroiodide (Pachycarpini
hydroiodidum)
N
CH2
N
HI
or
N
HI
N
d-Sparteine hydroiodide
The pachycarpine structure contains two fused quinolysidine cycles
White crystalline powder. Easily soluble in chloroform, soluble in
alcohol and water, difficult soluble in ether and acetone.
Pachycarpine is obtained from the aerial parts of
Sophora pachycarpa
Sophora pachycarpa
Storage
Drastic compound. In the
protected from light place.
Application
As ganglioblockator mean,
uterine muscle stimulant. Use
for
the
treatment
of
hypertension and spasms of
peripheral vessels in the
dosage of 0,05-01 g (oral); for
the
uterine
muscle
stimulantion – 3-5 ml of 3 %
solution (s/c, i/m).
Identification of pachycarpine hydroiodide
1. Substance gives reactions on iodides.
2. Allocation of the phachicarpine base which can be
identified by the following reactions :
3. а) by the formation of pachycarpine picrate (yellow
precipitate, melting point );
б) by the reaction of interaction with pairs of bromine and
ammonia on the filtrate paper - appears pink color after
heating:
R•HI + Br2 + NH3 R + NH4I + NH4Br + I2
4. With alkali solution of sodium nitroprusside - red-brown
fine crystalline precipitate which is dissolved in the excess
of HCl.
5. Specific rotation from +8,6° to +9,6° (7 % solution in
alcohol),
Quantitative determination of pachycarpine
hydroiodide
1.
Acid-base titration in nonaqueous medium, direct titration in the
presence of mercury (II) acetate, indicator - crystal violet
(Е=М.m/2).
2.
Argentometry, Fajans method, indicator - sodium eosinate
(Е=М.m).
Alkalimetry in alcohol medium by thymolphthalein в (Е=М.m).
Photocolorimetry.
3.
4.
Alkaloids – derivatives of quinoline
To this group alkaloids of quinine cortex belong – 24
alkaloids, the main representative of which is
quinine:
HC
CH2
HO
CH
H3CO
N
3 H2O
N
6'-Methoxyquinoline-(4')-[5-vinylquinuclidine-(2)]-carbinol
Quinine sulfate (Chinini
sulfas) Quinini sulfas*
HC
Quinine hydrochloride
(Chinini hydrochloridum)
Quinini hydrochloridum*
HO
CH
CH2
N
H3CO
HC
CH2
* H2SO4 * 2H2O
HO
N
CH
neutral salt
N
H3CO
* HCl *2H2O
N
neutral salt
Quinine dihydrochloride
(Chinini
dihydrochloridum)
HC
HO
CH
N
H3CO
* 2HCl
N
Acidic salt
Cinchona (Cinchona
Remija)
CH2
Obtaining
Cortex crushed and mixed with a mixture of lime and NaOH (for the
transferring of the alkaloids salts to the free basis), then extracted at
60-65оС by organic solvents. Extract washed by Н2SО4. From
aqueous solution occurs sediment - quinine sulfate, which is
purified by crystallization. Other alkaloids of cinchona cortex are
divided by the help of ion-exchange resins. From quinine sulfate by
exchange with salts of Ва2+ quinine salts are obtained.
Properties
Salts of quinine - colorless crystalline substances, odorless,
have very bitter taste. Gradually becomes yellow at the action of
light. All of them are left-rotation isomers.
Solubility
Qunine dihydrochloride - very easily soluble; quinine
hydrochloride - soluble, and quinine sulfate - a little soluble in
water.
Identification of quinine salts
1. Distinguished reaction - on anions of the corresponding
salts: chlorides or sulfates.
2. Reaction on alkaloids with Dragendorph.
3. Solutions of all quinine salts at the acidification by dil.
H2SO4 give blue fluorescence in UV - light.
4. Specific rotation of 3 % solutions of salts in 0,1 М
solution of hydrochloric acid by the calculation on dry
basis is : quinine dihydrochloride - 225°; quinine
hydrochloride - 245°; quinine sulfate - 240°.
5. At the interaction of alcohol solution of salt, acidified by
H2SO4, with alcoholic solution of iodine formed
characteristic (as leaves), green crystals of herepatite
4C20H24O2N2 · 2H2SO4 · 2HI · I4 · 6H2O.
6. The general reaction - thaleyoquine test: to the solution
of quinine salt add a few drops of bromine water and
ammonia - appears emerald green color:
HC
HC
CH2
Br
HO
HO
CH
N
O
Br2
H3CO
N
HC
CH2
OH OH
HO
CH
N
HN
Thaleyoquine
Òàë åé î õ³í
N
N
NH4OH
O
N
NH
CH
CH2
Br
7. Erythroquine reaction. At the action of bromine water and potassium
hexacyanoferrate (ІІІ) in alkali medium on the quinine solution red
color appears. This reaction is in 10 times more sensitive then
thaleyoquine, but color quickly disappears.
R
H3CO
O
5
R
H3CO
-
Br2; OH ; K3[Fe(CN)6]
7
H
N
R
O
H
N
R
O
H3CO
H3CO
7
N
H
N
R - õ³í óê ë ³äè í î âè é ô ðàãì åí ò õ³í ³í ó
O
- H2
R-quinuclidine fragment of quinine
R
H3CO
5
Åð³òðî õ³í
N
Erythroquine
Quantitative determination of quinine salts
Gravimetric method which based on the precipitation of
quinine base by the NaOH solution, its extraction by
chloroform and weighing of the residue obtained after the
distillation of chloroform. Percentage content by the
calculation on the dry matter is calculated by the
following formula:
X = (mв.ф.•F•100)/mhatch.  100/(100-В)
F – gravimetric factor, F = М.mquinine salt/М.mquinine base
В – mass fraction of moisture , %
2. Quinine salts in the medical forms are determined by
alkalimetry in neutralized by phenolphthalein mixture of
alcohol and chloroform :
X • HCl + NaOH  X + NaCl + H2O (Е = М.m.)
(X)2 • H2SО4 + 2NaOH  2X + Na2 SО4 + 2H2O
(Е = М.m./2)
3. Acidimetry in nonaqueous medium.
4. Bromatometry, direct titration. (Е = М.m./2).
KBrO3 + 5KBr + 6HCl → 3Br2 + 6KCl + 3H2O;
HC
HC
CH2
Br
CH2
Br
HO
HO
CH
N
CH
Br2
H3CO
N
H3CO
.
N
N
Purity test
The specific impurity in quinine hydrochloride is
barium – solution acidified by HCl, should not become
turbid within 2 hours after the adding of dil. H2SО4.
Storage
In tightly closed container, which keeps from action of light.
Aplication
Antimalaral medicine. Stimulant of uterine muscles
(quinine sulfate and quinine hydrochloride).
Quinine sulfate: powder, tabl. 0,15 and 0,5 g; 1,0-1,2 g per
day internally for the treatment of malaria.
Quinine hydrochloride: tabl. 0,25 and 05 g; Quinine
dihydrochloride: 50 % solution 1,0 ml
Thank you for attention!