Lecture 25
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Lecture №25. Alkaloids indol’s derivatives, purine alkaloids and their salts; some synthetic analogues according to the biological action as substances of the medical drugs and components of the dosage forms. Ass. Medvid I. I.

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Lecture №25

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Lecture №25

Alkaloids indol’s derivatives, purine alkaloids and their salts; some synthetic analogues according to the biological action as substances of the medical drugs and components of the dosage forms.

Ass. Medvid I. I.

Indole - condensed system of pyrrole and benzene cycles which have two share atoms:Indoleisastructuralbasisof physostigmine, strychnine, reserpine alkaloids.

Group reaction on indole derivatives – Van-Urk’s reaction

  • In the base of reaction is the process of electrophyllic substitution. Reagent p-dimethylaminobenzaldehyde. Reaction conducts at the presence of conc. H2SO4 andFeCl3as oxidant.

  • Derivatives of indole which have free 2 and 3 positions give this reaction. Reserpine gives this reaction by the opening of ring C in the presence of acids, as a result position 2 becomes free.

  • Product of reaction can exist in 2 forms. Color of the reaction product depends on the chemical structure of primer compounds conditions of the reaction. Van-Urk’s reaction can be hold with another aldehyde. So, for reserpine solution of vanillin in chloride acid is used.

Physostigmine salicylate (Physostigmini salicylas)Eserini salicylas

Salicylate of ester of methylcarbaminicacid and eseroline or 5-methylcarbaminoiloxy-1,3,1’-trimethyl-2,3,2’,3’-tetrahydropyrrole indole

Physostigmine– themainalkaloidof calabaricbeans(Fabacalabarica) – poisonousseedsofWestAfrican plant Physostigmavenenosus , Fabaceae


  • Physostigminesalicylate-brilliantcolorlessor almost colourlessprismaticcrystals. Solubleinwater, easilysolubleinalcohol, practically insoluble in ether. Aqueous solutions are unstable. It melts at about 182 °C, with decompositionOptic active compound. When heated with water easy hydrolyze and therefore its solutions for parenteral usage produce in aseptic introductions. On the air and light product paints in the red color – pharmacological inactive rubrezerine formed.

    Pharmacologicalaction cased by the methylurethane group.

    Proserine - white crystalline powder with bitter taste. Very easily soluble in water, easilysoluble in alcohol and chloroform, ether. Hygroscopic. Becomes pink on the light.

Identification of Physostigminesalicylate

  • Melting point, the specific rotation.

  • Substance gives reaction to salicylates (2 reactions in SPU).

  • TotalPharmacopeialreactionon alkaloids (withDragendorff's reagent)

  • After evaporation of the preparation with ammonium forms blue residue (physostigmine base), which is dissolved in ethanol with formation of a blue solution which after the acidification by СН3СООН becomes red.

  • Drug solution in H2SO4conc. gradually becomes yellow.

  • Erdman and Frede reagents with medication give reddish-yellow color, withHNO3conc. – yellow color.

7. When heated with alkalis (and gradually when heated with water)physostigminesalycilate hydrolyzed and appears character odor methylamine:

8. At the heating with 0,1 % ninhydrine solution in conc. H2SO4on the water bath at 60 0С during 10 min. And than after cooling solution have green fluorescence. Proserine gives blue fluorescence at this conditions.

9. At the gradually adding to the solution boric acid, 0,1 М solution of nitrate acid and sodium nitrite, after 1 min. add sodium hydroxide solution, violet color appears.

Assay Physostigminesalicylate

  • Alkalimetriya, direct titration. The drug is dissolved in a mixture of ethanol and chloroform and titrated by 0,1 М NаОНto the pink color (indicator – phenolphthalein). Е = М.m.

  • Acidimetry in non-aqueous medium.The drug is dissolved in a mixture of chloroform and conc. CH3COOH, titrated by 0,1 М НClО4. For determination of the end-point use potentiometry. Equivalent point is fixed by potentiometric method. Е = М.m./2.

  • Complexonometry, reverse titration.As a stable titrant acetic-acidic solution of bismuth nitrate is used in the presence of potassium iodide. Scheme of reaction:

    Product of the interaction is filtrated and an excess of reagent is titrated by 0,1 М sodium EDTA solution. Е = М.m.

STORAGEand USAGE of Physostigminesalicylate

In an airtight containers of dark glass, protected from light. Poison compound.

Cholinesterase inhibitor, myotic mean (atropine antagonist). Used for the treatment of glaucoma as 0,25-1% eye drops. Introducesubcutaneous 0,1% -1,0 solution the neuromuscular diseases (Alzheimer's disease). H. d. – 0,0005 g, H. d. d. – 0,001 g.

Synthetic substituteof physostigmineProserine (Proserinum) Neostigmine methylsulfate*

N-(m-dimethylcarbamoiloxiphenyl)-N,N,N-trimethylammonium methylsulfate

Identification of proserine

  • Reactiontomethylsulfate-ion. If after heating the drug withHNO3 conc. add solution ofBaCl2, white precipitatefalls (BaSO4).

  • With a solution of iodine preparation forms brown sedimentof periodide.

  • At the heating of drug with alkali dissolution of urethane grouptakes place (m-dimethylaminophenol formed, which is detected by the condensation with diazotativesulfanylic acid – cherry-red color (azo-dyes)):


The modified K'yeldal method.The drug is boiled in a K'yeldal flask with NaOH. Dimethylamine, which evaporates, distilled with water vapor in the receiver with a solution of boric acid. Metaborate and tetraborate of dimethylamine formed, which are titrated by 0,1 М solution of HCl (mixed indicator). Е = М.m.

STORAGE and USAGE of proserine

In an airtight containers of dark glass, protected from light. Poison compound.

Substitute of physostigmine. Anticholinesterase, antimyasthenic mean. Curare antagonist drugs. Used for treatment of myasthenia, paralysis, neuritis, atony of intestine and urinary bladder, glaucoma, for stimulating labor activity as 0,25-1% as eye drops.

Issue– tablets 0,015 g, amp. 0,05%-1,0.

H. d.,internally – 0,015 g, H. d. d.,internally – 0,05 g; H. d. subcutaneous – 0,002 g, H. d. d. s/c – 0,006 g.

Cycles АВ, BD, ED – derivatives of indole.

Cycle А – aromatic and strychnine can be nitrated and halogenated.

N19 – tertiary atom, has a base character and gives salts with acids.

N9 – is in the lactam group, which may be disclosed by the interaction with alcohol solution of KOH with formation of carboxyl and secondary amino-groups.

Strychnine nitrate (Strychnini nitras)

Strychnine can be found with brucine in the seeds of tropicalplant Strychnos Nux Vomica (emetic nut)

Reserpine (Reserpinum)


Reserpine molecule contains indole(АВ), dihydroquinolysidine (СD),

partially hydrogenated3-carbolynic (АВС), hydrogenatedisoquinoline (ED) cycles.


Reserpine contains in the roots of the plantRauwolfia serpentina Benth

Physical properties

Strychninenitrate - acolorlessbrilliantcrystals with verybittertaste. Difficultlysolubleinwaterandalcohol, easilysolubleinboilingwater, practically insoluble in ether.

  • Reserpine - colorless, white or slightly yellow, small crystals or crystalline powderwith melting point 261-265°С. Insoluble in water, soluble in chloroform, acetone, pyridine and ether, darkening slowly on the exposure to

  • light. Optic active compound. At the heating with acids or alkalis hydrolysis takes place (reserpinic acid, methanol, trimethoxybenzoic acid form).

Identification of strychnine nitrate

  • Pharmacopeial reaction on alkaloids.

  • Solution of the drug in H2SO4conc. + crystal of K2Cr2O7– formed the blue-violet strips which pass into the red and lilac-green.

  • Vitali-Moren’s reaction. At the interaction with HNO3 conc. drug becomes yellow (as opposed to brucine, which becomes blood-red) by nitration of benzene cycle А; after the evaporation of reaction product the residue gives with alcohol solution of КОНformed red-violet color.

  • Van-Urk’s reaction (on indole cycles). With 1% vanillin in glycerol in the presence of H2SO4dil. Pink-violet colorappears.

5. Reaction on nitrate ions NO3–-:

а) SPU. The interaction with nitrobenzene in the presence of sulfate acid

Quantity of substance, listed in a separate article, add to the mixtureof 0,1 mlof nitrobenzolRand 0,2 ml of sulfate acid Randafter 5 min. cooled in ice water. Continuing to cool slowly and while stirring add5 ml of water R, 5 mlof sodium hydroxide concentrated solution R NaOH, 5 mlof acetone R, shake and put for standing; the apper layer becomes dark purple.

b) SPU, N. Not discolors potassium permanganate

The solution of the substance, acidified by acid sulfate diluted RH2SO4, not discolors solution of 1 g/lpotassium permanganate R(difference of nitrite).

с) Not pharmacopeial reaction. Interaction with iron (ІІ) sulfate FeSO4 in the medium of conc. H2SO4; brown ring is formed(FeSO4NO) (on the clock glass):

2 Strychnine•НNO3 + 6FeSO4 + 4H2SO4 = 2NO + 3Fe2(SO4)3 + (Strychnine)2•Н2SO4 + 4H2O

NO + Fe2+ + SO42–[Fe(NO)]SO4

d)Unpharmacopeial reaction. Interaction with diphenylamine in acidic medium. (conc. H2SO4),formed an bright blue organic dye:


Sulfimmonium salt of diphenylbenzidine (blue dye)

Identification of reserpine

  • Specific optical rotation (6 assymetric carbon atoms).

  • UV-spectroscopy (chromophor groups – indole andtrimethoxybenzoatic acid – 2 maximum of absorption on UV-spectrum).

  • Reactions of indole cycle. With chloric water –purple, withKMnO4– dark lilac, with vanillin in the presence of HCl - pink, with Н2О2 – yellow-lilac color.

  • Water solutions of reserpine in UV-light – blue fluorescence.

  • Alcohol solution of the preparation + H2SO4 + NaNO2 – green fluorescence.

  • With Frede reagent – red color, which goes to the blue.

  • On ester groups:

    а) alkali hydrolysis;

    б)hydroxame sample.

  • Van-Urk’s reaction. With p- dimethylaminobenzaldehyde + H2SO4+СН3СООН – green coloring that goes into the red. With vanillin in chloride acid – pink color.


Strychnine nitrate – Alkalimetry, direct titration. Titration of the drug in alcohol-chloroform solution of 0,1 М NaOH (phenolphthalein indicator).

Е = М.m.

Specificadditive - brucine.

Reserpine – Acidimetry in non-aqueous medium.Hatch is titrated in the medium of anhydrous СН3СООН by 0,1 М solutionHClO4 (indicator crystal violet) to the appearance of green color. Е = М.m.

Strychnine nitrate

In airtight containers. Poison compound.

CNS stimulant, tonic mean.

Issue - amp. 0,1%-1,0.

H. d. s/c – 0,002 g; H. d. d. s/c – 0,005 g.


In airtight containers, in a dark place. Powder - poisonous substance.

Neuroleptic, treatment of hypertension. Included in tablets: Adelphane (0.1 mg of reserpine,10 mgof dihydralasine), Adelphan–esidrex(Triresid) (Adelfane + 10 mg ofdichlorothiazide), Adelphane–esidrex-К (Triresid К)(0,6 g ofКСl), Crystepin, Neocrystepin. Raunatine–the amount of Rauwolfia alkaloids.

Storage, usage

Alkaloids, purine derivatives Purine –condensed system of pyrimidine and imidazol

If in the core of purine hydrogen atoms in the pyrimidine nucleus replaced by hydroxyl groups, we will get xantine:

Caffeine is contained in coffee beans (Coffeaarabica), tea leaves (Theasinensis), cola (Cola acuminata)


Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.


Theophylline first was isolated from tea leaves (Theasinensis)

Theobromine is extracted from cocoa beans (Theobroma cacao)

Three natural alkaloids, derivatives xantine: caffeine, theophylline, theobromine:

Extracted from semi-synthetic uric acid, guanine and urea.

Very convenient is the method of extraction of caffeine and theobromine from xantine, which can be extracted from uric acid (waste poultry farms) and guanine (fish flakes, waste of paper):

Synthesis of caffeine and theophyllin by method Hmelevskiy - Abramova( firs was synthesed by Traube in1900 year).

Caffeine (Соffеіnuт), Caffeinemonohydrate (Соffеіnuт monohydricum) (SPhU)

1,3,7-Trimethyl-3,7-dihydro- 1H-purine-2,6-dione


Caffeine-sodium benzoate (Coffeinum-natrii benzoas)

Caffeine Medications

Caffeine - White or almost white, crystalline powder or silky crystals, sublimes readily.Moderately soluble

in water, freely soluble in boiling water, slightly soluble in ethanol and ether. Soluble in the concentrated solutions of alkali benzoate or salicylates. Very weak base, forms unstable salts with acids by nitrogen in position 9.

Caffeine-sodiume benzoate –white powder, odorless, bitter taste.

Easily soluble in water, slightly soluble in ethanol. Contains 38-40% caffeine.

Extracted by the mixing and evaporation to the dry state of aqueous solutions containing equimolar quantity of caffeine and sodium benzoate.


General Pharmacopeial reaction - a reaction on xantines (Murexide reaction or reaction on purine alkaloids):

Identification of caffeine

  • By the physico-chemicalconstants: meltingpoint, IR-spectroscopy.

  • With potassium iodide in iodine in the presence of HCldil.- brown precipitate formed(periodide С8Н10N4О2•J2•HJ), which dissolves in NaOH dil. solution at the neutralization.

  • Murexide sample.

  • Unpharmacopoeial reaction - with 1% solution of tannin – white precipitate dissolved in excess of reagent.

  • With HgCl2 – white crystalline sediment, which is a complex compound with the following content C5H10N4O2· HgCl2.

  • Withacetylacetone and dimethylaminobenzaldehyde. Solution of the substance in a mixture of acetylacetone and dil. NaOH heated in a water bath, cooled, than add solution of dimethylaminobenzaldehyde and heat again, cool and add water - appears an intense blue color:

Caffeine monohydrate gives all reactions on caffeine after a preliminary drying at 100-105 ° C.

Identification of caffeine-sodium benzoate

1. Caffeine identify by:

a) melting temperature (234-237 ° C) after extraction by chloroform from alkaline solution;

b) Murexide sample;

c) reaction with 1% solution of tannin;

d) reaction with iodine solution;

2. Sodium benzoate identify by:

e) the reaction with solution of iron (III) chloride - pink-yellow sediment;

f) the sodium cation paints the flame in yellow color.


Acidimetry in non-aqueous medium in a mixture of acetic acid anhydrous, acetic anhydride and toluene, a direct titration. Potentiometric indication, the control experiment (Е=М.m).

Iodometry, reverse titration, indicator - starch(Е=М.m/4).

Cerimetry, reverce titration, with iodometric ending. An excess of cerium is neutralized by potassium iodide solution. Sodium thiosulfate used as titrant. (Е=М.m/4).

Caffeine-sodium benzoate

Caffeine content is determined by iodometric method (Е=М.m/4). ). In the dry matter it should be 38,0 - 40,0 %.

Sodium is determined in the presence of mixed indicator (methyl orange solution and methylene blue at a ratio of 1:1) and ether (for the extraction of benzoic acid, available in the titration) (Е=М.m). Sodium benzoate in the dry matter must be not less than 58,0 % and not more than 62,0 %.


Cerimetric determination of caffeine

2 Ce(SO4)2 + 2 KI  I2 + K2SO4 + Ce2(SO4)3

I2 + 2 Na2S2O3  2 NaI + Na2S4O6


In a dry, dark place.

Central nervous system stimulant,cardiotonic mean, at the angiospasms; enuresis in children; stimulant of mental and physical disability, poisoning with drugs. Produced as powder.

Caffeine monohydrate is part of the tablets: Theophedrine, Cytramone, Cytropak, Askofene, Cofficyll, Cophetamine,Benalgin, Coldrex, Solpadein, Panadol-екстра. Applyindosesby 0,05-0,1 gas CNS stimulant.

Caffeine-sodium benzoate

In a dry, dark place.

Central nervous system stimulant,cardiotonic mean. Thanks to the solubility in water used in the form of injection solutions. Issue - powder, tablets 0,1 and 0,2 g, 0,075 g (for children); 10% і 20% solutions in amp. by 1,0-2,0 ml. Included in the tablets: Anaprylline, Pentalgin.

Storage, Usage

TheobromineTheobrominum (SPhU)

3,7-Dimethyl-3,7- dihydro-1Н-purine-2,6-dione, or 3,7- dimethylxantine

Theophylline monohydrate Theophyllinum monohydricum (SPhU)

1,3-Dimethyl-3,7- dihydro-1Н-purine-2,6-dionemonohydrate, ormonohydrate of 1,3- dimethylxantine


White crystalline powder, with bitter taste. very slightly soluble in water, ethanol ,ether and chloroform; slightly soluble in hot water; easily in dil. Solutions of alkalis and acids.


White crystalline powder. Sightly soluble in water, ethanol and chloroform; easily soluble in hot water; soluble in dil. Solutions of acids and alkalis.


Theobromine and theophylline - amphoteric compounds with a predominance of acidic properties (by moving the hydrogen atom at the nitrogen atom in position 1 or 7).

Identification of theobromine

  • IR-spectrophotometry.

  • Dissolve the substance in ammonium solution at the heating. After cooling add silver nitrate solution – solution must still be colorless. After the boiling during few minutes white precipitate formed.

  • Reaction on xantines (murexide sample). At the oxidation of theobromine 3-methylalloxane and methylurea formed. Ammonium salt of dimethylpuepuric acid formed as a result of murexide reaction:

Unpharmacopoeial reactions

  • Reaction of the sodium salt of theobromine, obtained by the interaction of alkali with an excess of preparation, with cobalt (II)chloride solution – intense violet color appears, which quickly disappears, grey-blue precipitate:

  • The reaction of theobromine sodium salt with silver nitrate - formed a dense gelatin mass (silver salt), which is thinning by heating to 80° С and solidifies again at the cooling.

  • WithHgCl2 – white crystalline precipitate.

Identification of theophylline

  • Determination of the melting temperature alter the drying.

  • IR spectrophotometry.

  • Theophylline in the alkali medium decomposes to teophyllidine, which can be identified by the reaction of azojoining with diazonium salts, red color azo-dye formed.

  • Determination of the water by semimicromethod(К. Fisher) (8-9,5 %).

  • Reaction on xantines (murexide sample). At the oxidation of theophylline1,3-dimethylalloxane and urea. Ammonium salt of tetramethylpuepuric acid forme as a result of murexide reaction:

  • The reaction of theobromine sodium salt obtained by the interaction of alkali with an excess of drug, with a solution of cobalt (II) chloride - formed white with pink tinge precipitate of cobalt salt.

  • WithHgCl2 –white crystalline precipitate.

  • With alkali solution of sodium nitroprussidegreen color formed dissappearsat the adding an excess of acid.

  • The reaction of theobromine sodium salt with silver nirate - formed a dense gelatin mass.

  • Theophylline with 2,6-dichloroqiunonechloroimide in borate

    buffer solution

    (рН 8,5) gives intense blue

    merocyanic dye:

AssayTheophylline and TheobromineAlkalimetry by the substituent(indirect alkalimetry).Indicator – phenolphthalein (theobromine) orBromothymol blue (theophylline). Е = М.m.


In airtight containers, place protected from light.

Stimulates the activity of the heart, somewhat expands the coronary vessels and bronchi, shows diuretic effect. Issue - powder and tablets by 0,25 g.

Included in tablets: Theminal(with amidopyrineand Phenobarbital), Theodibaverine(withpapaverine and dibazole), Theoephedrine.


In airtight containers, place protected from light.

Non-selective phosphodiesterase inhibitor (xanthine); treatment of reversible airways obstruction. Broncholitic, cardiotonic and diuretic mean with moderate influence on the stagnation phenomena in the cardiac and renal origin organs. Issue – powder and tablets by 0,1 and 0,3 g; amp. 2%-5,0; candles by 0,2 g. Teopek, Theotard, Neophylline, Euphylline.Included in tablets: Theoephedrine.

Storage, usage

Pentoxifylline (Pentoxifyllinium)Agapurine, Pentyline, Trental A synthetic analogue of theobromine

3,7-dimethyl-1-(5’-oxohexyl)-3,7-dihydro-7Н-purine-2,6-dionor 1-(5’-oxohexyl)-theobromine

Identification of pentoxifylline

  • Temperature of melting

  • IR-spectroscopy

  • TLC

  • Reaction on xantines

  • Formation of azo-dye (look theophylline)



    Acidimetryinnon-aqueousmediainamixtureofanhydrousaceticacidandaceticanhydride,directtitration. Potentiometricindication. (Е=М.m).

Usage of pentoxifylline

Has a vasodilator effect, improves tissue oxygen supply, decreases thrombosis aggregation and reduces blood viscosity.Apply at the peripheral circulatory disorders, atherosclerotic disorders, ischemic condition after heart attack, in ophthalmology, at the hearing disorders. Issue – tablets of 0,1 g, ampoules of 2%-5,0. Adopt inside by 0,2 g 3 times daily after meals. In the acute disorders of peripheral or cerebral circulation injected 0,1 gintravenousin 250-500 ml ofNaClor 5% glucose solution.

Synthetic analogues of theophylline

Theophylline-ethylenediamine (Theophyllinum et ethylenediaminum) (SPhU),

Euphylline (Euphyllinum), Aminophilline

Theophylline with 1,2-ethylenediamine

White, sometimes with yellowish crystalline powder with slight ammonia odor. On the air absorbs carbon dioxide, thus decreasing its solubility. Soluble in water, aqueous solutions have an alkaline reaction.

Identification of euphylline

1.Theophylline is identified after the separation by HCl of ethylenediamine according to SPhU:

а) By the melting temperature of theophylline (269 - 274°С) after HCl acidification to рН 4-5;

b) IR-spectroscopy;

c) Reaction of azojoining (look theophylline);

d) murexide sample.

2.Ethylenediamine can be confirmed by the following reactions:

а) determination of the melting temperature of the product of reaction with benzoyl in alkali medium (dibenzoylethylenediamine) (SPhU):

b) with a solution of copper (II) sulfate a bright purple color forms :

c) with 2,4-dinitrochlorobenzene –yellow precipitate falls.


  • Ethylenediamine can be determined by acidimetry, indicator –methyl orange. Е = М.m./2.

    Ethylenediamine in euphylline should be 13,5—15 % in the dry matter.

    2. Theophyllinecan be determined by alkalimetry by substituent 1 after drying in a drying cabinet at 25-130 °С to the disappearance of amine odor.

    The content of waterless theophylline in euphylline should be 84- 87,4 %.

Storage, usage of euphylline

Given the ability to absorb carbon dioxide, stored in a well corked filled to the end container, protected from the effects of light and moisture.

Antispasmodic, bronchodilatin, diuretic mean. At the bronchial asthma and bronchospasm, hypertension, cardiac asthma, to improve blood circulation to the brain, decreasing the intraperitoneal pressure and brain edema in ischemic stroke.

Used oral by 0,15gafter food, i/v (2,4% solutions by 5,0) andi/m (24 % solution by 1 ml).


Less toxic than theophylline. Used for treatment of coronary spasm, cardiac and bronchial asthma, hypertension. Issue – tablets by 0,2 g; amp. 10%-5,0; candles by 0,5 g.

Diprophylline (Diprophyllinum)


Used to improve peripheral and cerebral circulation

Issue – tabletsby 0,15 g; amp. 15%-2,0 і 10,0.

Xantinolenicotinate (Xantinoli nicotinas) Complamine, Theonicol


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