Lecture №23

LectureLecture №23 №23

Alkaloids as medicines. Sources of Alkaloids as medicines. Sources of obtaining, methods of the structure obtaining, methods of the structure

determination. Their chemical determination. Their chemical classification, general methods of classification, general methods of

qualitative and quantitative qualitative and quantitative determination. Alkaloids, imidazole’s, determination. Alkaloids, imidazole’s,

pyrolysidine’s, quinolysi(di)ne’s, pyrolysidine’s, quinolysi(di)ne’s, quinoline’s derivatives, with exocyclic quinoline’s derivatives, with exocyclic

nitrogen atom.nitrogen atom.

ass.ass. Medvid I.I.Medvid I.I.

Definition Definition of of alkaloids: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 natureDistribution in nature::Alkaloids, related by structure, often can be found Alkaloids, related by structure, often can be found in plants that are close in botanical terms. Mainly in in plants that are close in botanical terms. Mainly in one plant is a mixture of alkaloids (exception – one plant is a mixture of alkaloids (exception – castor plant containing ricynine). Some plants castor plant containing ricynine). Some plants (cinchona, poppy seeds, barberry) containing up to (cinchona, poppy seeds, barberry) containing up to 10-15% of alkaloids.10-15% of alkaloids.

Localization - most aerial parts of medicinal plants Localization - most aerial parts of medicinal plants (flowers, fruits, leaves, cortex). Some alkaloids can (flowers, fruits, leaves, cortex). Some alkaloids can be moved from one part of plant to another part. be moved from one part of plant to another part. Their content in plants depends on the: climate, Their content in plants depends on the: climate, temperature, altitude above the sea level and temperature, altitude above the sea level and others. So the content of ephedrine in Ephedra others. So the content of ephedrine in Ephedra may change during the year from 0.3% to 2,5%.may change during the year from 0.3% to 2,5%.

Historic moments of alkaloid Historic moments of alkaloid chemistry research:chemistry research:

In 1804 the French pharmacist Sehen allocated In 1804 the French pharmacist Sehen allocated morphine from opium as a technical product.morphine from opium as a technical product.In 1816 professor of the Kharkiv University In 1816 professor of the Kharkiv University F.I. Giza allocated quinine. In 1818 year were F.I. Giza allocated quinine. In 1818 year were discovered strychnine and brucine, and a year discovered strychnine and brucine, and a year later - caffeine.later - caffeine. InIn 1842 1842 y y. А.А. . А.А. Voskresenskiy Voskresenskiy opened opened theobrominetheobromine, , and in 1847 J.F. – Fritzsche - and in 1847 J.F. – Fritzsche - hormynhormyn..A.M. Butlerov and A.N. Vishegradskiy on the A.M. Butlerov and A.N. Vishegradskiy on the basis of their experimental work concluded that basis of their experimental work concluded that all alkaloids are derivatives of pyridine and all alkaloids are derivatives of pyridine and quinoline.quinoline.

InIn 1881 1881 yy. . inin Russia first synthesis of coniine was Russia first synthesis of coniine was conducted.conducted.

1915 1915 yy. – . – Chychybabin with Rodionov began Chychybabin with Rodionov began industrial production of opium and other alkaloids. industrial production of opium and other alkaloids. InIn 1917 1917 y. first alkaloid plant began work in Russia.y. first alkaloid plant began work in Russia.

Important role in the development of chemistry Important role in the development of chemistry played A.P. Orekhov and his school.played A.P. Orekhov and his school. They They investigated 1500 species of plants, found more investigated 1500 species of plants, found more than 250than 250 alkaloid containing plants, issuedalkaloid containing plants, issued monograph "Chemistry of alkaloids”.monograph "Chemistry of alkaloids”.

NN.А. .А. PreobrazenskiyPreobrazenskiy in 1933 at first made the in 1933 at first made the original synthesis of pilocarpine.original synthesis of pilocarpine.

Classification of alkaloidsClassification of alkaloids AlkaloidsAlkaloids are naturally occurring chemical compounds containing basic are naturally occurring chemical compounds containing basic

nitrogen atoms. The name derives from the word alkaline and was used to nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects alkaloids are toxic to other organisms. They often have pharmacological effects and use as medications and recreational drugs. Examples are the local and use as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste. morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste. Alkaloids are usually classified by their common molecular precursors, based Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was 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 known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were 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 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 changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.biologically-important amine that stands out in the synthesis process.

Types of the alkaloid classifications • By the chemical structure:1) derivatives of pyrrolidineyrrolidine (sthrahidrine, turicine)2) derivatives of tropane (atropine, cocaine)3) derivatives of pyperidinepyperidine (lobeline, coniine)4) derivatives of pyridine (nicotine, anabasine)5) derivatives of pyrrolysidine (platyphylline)6) derivatives of quinolysidine (pahicarpine, lupinine)7) derivatives of quinoline (quinine)8) derivatives of isoquinoline (papaverine, morphine)9) derivatives of indol (reserpine, strychnine)10) 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 (platyphyllineplatyphylline hydrotartrate):

NN

H

• Derivatives of pyridine (nicotine) and piperidine (lobeline, coniine):

N N

H

• Condensed pyrrolidine with piperidine (tropane):

3N CH

• Derivatives of quinolysine (cytisine) and quinolysidine (pachycarpine hydroiodide):

N N

• Derivatives of quinoline (salts of quinine) and isoquinoline (papaverine hydrochloride, opium alkaloids):

NN

• 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

N

N

H

• 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 materialsMethods of extraction from plant materials

extraction in the form of salts (water, extraction in the form of salts (water, alcohol, tartaric acid); alcohol, tartaric acid);

extraction in the form of basis extraction in the form of basis (NH(NH44OH, OH,

NaHCONaHCO33););

Distillation of Distillation of alkaloids bases with alkaloids bases with aqueous steam (boiling point for which is aqueous steam (boiling point for which is less than 100 º C).less than 100 º C).

Extraction as salts:Extraction as salts: to raw material add water or to raw material add water or ethanol with few drops of tartaric acid. All alkaloids ethanol with few drops of tartaric acid. All alkaloids forms salts with tartaric acid. For purification to this forms salts with tartaric acid. For purification to this extract add base and all alkaloids form bases, which extract add base and all alkaloids form bases, which obtained by organic solutions. Operation of obtained by organic solutions. Operation of purification repeat few times. Then solvent purification repeat few times. Then solvent separated from alkaloids. Sum of alkaloids is separated from alkaloids. Sum of alkaloids is separated on individual compounds.separated on individual compounds.

Extraction as bases:Extraction as bases: to raw material add alkali to raw material add alkali solution (ammonium, sodium hydrocarbonate or solution (ammonium, sodium hydrocarbonate or carbonate). Alkaloids bases are extracted by organic carbonate). Alkaloids bases are extracted by organic solutions. Purification realize by transferring solutions. Purification realize by transferring alkaloids to salts and then to bases. Operation of alkaloids to salts and then to bases. Operation of purification repeat few times. purification repeat few times.

The methods of separation of the The methods of separation of the selected amount of alkaloids:selected amount of alkaloids:

Fractional distillation in vacuumFractional distillation in vacuum;;By the different solubility of alkaloids By the different solubility of alkaloids – – salts and basessalts and bases;;By the By the different power of basic properties of different power of basic properties of alkaloids;alkaloids;

based on the featuresbased on the features of chemical propertiesof chemical properties;;By the different ability to adsorption By the different ability to adsorption (chromatography(chromatography););Method of anticurrent Method of anticurrent separationseparation..

For identification of alkaloids use general, For identification of alkaloids use general, group and specific reactiongroup and specific reaction..

The general reactions conduct with common The general reactions conduct with common alkaloid precipitation and special reagents.alkaloid precipitation and special reagents.

General precipitate reactions based on the General precipitate reactions based on the ability of alkaloids as bases to give simple or ability of alkaloids as bases to give simple or complex salt with different, more often complex salt with different, more often complex acids, salts of heavy metals and complex acids, salts of heavy metals and others.others. These products are usually not soluble These products are usually not soluble in water, so calledin water, so called precipitate.precipitate.

General alkaloid precipitate reagentsGeneral alkaloid precipitate reagents:: Dragendorph reagentDragendorph reagent – BiI – BiI33+KI↔K[BiI+KI↔K[BiI44] - ] - SPUSPU

Lyugol, Vagner, Bushard reagentsLyugol, Vagner, Bushard reagents– – sol. sol. І І22 inin КІ КІ in different concentraionsin different concentraions

Maier reagentMaier reagent – HgI – HgI22 + 2KI↔K + 2KI↔K22[HgI[HgI44]]

Marme reagentMarme reagent ( (solutionsolution CdICdI22 в в KIKI))

Zonnenshten reagent Zonnenshten reagent - Н- Н33Р0Р044 • 12Мо0 • 12Мо033 • 2Н • 2Н220 0

Sheibler reagent Sheibler reagent - Н- Н33Р0Р044 • 12 • 12WWоОоО33 • 2Н • 2Н2200

Berthran reagent - Berthran reagent - SiOSiO22 • 12 • 12WWо0о03 3 • 4Н• 4Н2200

5% Tannin solution (freshly prepared)5% Tannin solution (freshly prepared)..Saturated solution of picric acid.Saturated solution of picric acid.

Special (painted) reagents on alkaloids:Special (painted) reagents on alkaloids:

Conc. H2SO4.Conc. H2SO4. Conc. HNO3.Conc. HNO3. Erdman reagent (H2SO4 conc.+HNO3 conc.).Erdman reagent (H2SO4 conc.+HNO3 conc.). Phrede reagent ((NH4)2MoO4+H2SO4 conc.).Phrede reagent ((NH4)2MoO4+H2SO4 conc.). Marki reagent (HCOH+H2SO4 conc.).Marki reagent (HCOH+H2SO4 conc.). Mandelin reagent (NH4VO3+H2SO4 conc.).Mandelin reagent (NH4VO3+H2SO4 conc.). Sodium nitroprusside (Na2[Fe(CN5)No]Sodium nitroprusside (Na2[Fe(CN5)No]··2H2O).2H2O). Vazitsky reagent (solution of p-Vazitsky reagent (solution of p-

dimethylaminobenzaldehyde in conc. H2SO4).dimethylaminobenzaldehyde in conc. H2SO4).

Methods of the quantitative Methods of the quantitative determination of alkaloidsdetermination of alkaloids::

Acid-base titration in nonaqueous environmentAcid-base titration in nonaqueous environment – – for the for the quantitative determination of both salts and bases.quantitative determination of both salts and bases.Acid-base titrationAcid-base titration::

а) а) aacid-base titration, direct titration of acids and basescid-base titration, direct titration of acids and bases;;bb) ) acid-baseacid-base back-titration for determination of bases back-titration for determination of bases by reverse by reverse

titrationtitration;;cc) ) Alkalimetry – Alkalimetry – titration of alkaloids salts by alkali in water-alcohol titration of alkaloids salts by alkali in water-alcohol

medium in the presence of phenolphthalein (with or without medium in the presence of phenolphthalein (with or without the usage of organic solvent that does not move with water the usage of organic solvent that does not move with water for extraction of alkaloid bases)for extraction of alkaloid bases)

dd) ) Alkalimetry by the Alkalimetry by the substituentsubstituentGravimetric methodGravimetric method Methods based on individual chemical properties of alkaloids.Methods based on individual chemical properties of alkaloids.PhysicPhysico-o-chemical methodschemical methods..

Alkaloids with exocyclic nitrogen atom

HC

HC

OH

CH3

NHCH3

HCl

Ephedrine hydrochloride (Ephedrini hydrochloridum)

Sphaerophysine benzoate (Sphaerophysini benzoas)

1-guanidino-4-(isoamylene-11)-aminobutane dibenzoate

(-) 1-Phenyl-2-methylaminopropanol-1 hydrochloride

CH CH

H3C

H3C

CH

NH

CH2

CH2

CH2

CH2

NH

CNH

NH2

2 C6H5COOH

Ephedrine contains in different types of Ephedra, together with its

stereoisomers

L-ephedrine (cys-isomer, left-rotation)

D-pseudoephedrine (trans-isomer, right-rotation)

C C

H

OH

C6H5

HN

CH3

H

CH3

C C

OH

H

C6H5

HN

CH3

H

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:

HCH3C

Cl

CO

Cl

CC6H5

HC

O NHCH3

CH3

-HCl

(H)

CC6H5

HC

O Cl

CH3

HCC6H5

HC

OH NHCH3

CH3

-HCl

CH3NH2C6H6

Sphaerophysa salsula

Physical propertiesPhysical properties

Ephedrine hydrochlorideEphedrine hydrochloride CColorless needle crystals or olorless needle crystals or

white crystalline powder, white crystalline powder, odorless, with bitter tasteodorless, with bitter taste. . Easily soluble in water (so Easily soluble in water (so under the action of alkali under the action of alkali precipitate is not falls - the precipitate is not falls - the difference from other difference from other alkaloids), soluble in alcohol, alkaloids), soluble in alcohol, practically insoluble in ether.practically insoluble in ether.

Sphaerophysine Sphaerophysine benzoatebenzoate

White crystalline White crystalline powder with bitter powder with bitter taste. Soluble in taste. Soluble in water, alcohol, alkalis, water, alcohol, alkalis, insoluble in ether and insoluble in ether and chloroform.chloroform.

IdentificationIdentificationEphedrine hydrochlorideEphedrine hydrochloride

1.1. Reactions Reactions onon chloride chloridess

2.2. WithWith CuSOCuSO44 at the presence ofat the presence of NaOH – blue complex NaOH – blue complex compoundcompound ( (At the shaking of At the shaking of this solution with ether, ether this solution with ether, ether layerlayer paints in red-violet paints in red-violet colorcolor, , water layerwater layer keeps blue keeps blue colorcolor))..

3.3. At the heating with potassium At the heating with potassium ferrocyanide ferrocyanide crystal smell of crystal smell of benzaldehyde appears benzaldehyde appears ((bitter bitter almondalmond))..

4.4. Specific rotationSpecific rotation: : fromfrom -33° -33° toto -36° (5 -36° (5 % % water solutionwater solution). ).

Sphaerophysine Sphaerophysine benzoatebenzoate

1.1. With HCl – white With HCl – white precipitate of benzoic acid precipitate of benzoic acid falls. falls.

2.2. At the boiling with alkalis At the boiling with alkalis urea separated and thenurea separated and then NHNH33

3.3. With sodium nitroprusside With sodium nitroprusside alkali solutionalkali solution, , laterlater HClHCl – – cherry-red color which cherry-red color which quickly disappears.quickly disappears.

Quantitative determinationQuantitative determinationEphedrine hydrochlorideEphedrine hydrochloride

1)1) Acidimetric titration in Acidimetric titration in nonaqueous medium in the nonaqueous medium in the presence of mercury (II) acetate presence of mercury (II) acetate ((indicatorindicator crystal violetcrystal violet, , Е=М.Е=М.mm).).

2)2) Alkalimetric titration Alkalimetric titration alcohol-alcohol-chloroform medium chloroform medium (Е=М.(Е=М.mm).).

3)3) Argentometry by the linked HCl Argentometry by the linked HCl ((Fajans’ methodFajans’ method with the usage with the usage of bromothymol blue indicatorof bromothymol blue indicator) ) (Е=М.(Е=М.mm).).

Sphaerophysine Sphaerophysine benzoatebenzoate

1)1) Acidimetric titration in Acidimetric titration in nonaqueous medium in the nonaqueous medium in the presence of ice acetic acid presence of ice acetic acid ((indicatorindicator crystal violetcrystal violet, , Е=М.Е=М.mm/2)./2).

2)2) BromatometryBromatometry, , direct direct titrationtitration (Е=М. (Е=М.mm/2)./2).

Storage, applicationStorage, applicationEphedrine hydrochlorideEphedrine hydrochloride

Drastic compoundDrastic compound. . In In tightly closed container (TCC) tightly closed container (TCC) whichwhich keeps from the action of keeps from the action of lightlight..

Sympathomimetic Sympathomimetic ((vasoconstrictivevasoconstrictive, , bronchodilatingbronchodilating)) mean mean. . By the By the action it is close to adrenalineaction it is close to adrenaline, , has specific stimulatory action has specific stimulatory action on CNSon CNS. . InternallyInternally byby 0,025- 0,025-0,050,05gg 2-3 2-3 timestimes perper dayday, , ii//mm oror ii//v (intravenous)v (intravenous) byby 1 1 ml ofml of 5% 5% solutionsolution. . Included to the content Included to the content of Theophedrine tabletsof Theophedrine tablets,, EphatineEphatine aerosolaerosol, , Solutan and Solutan and Broncholitine syrupsBroncholitine syrups..

Sphaerophysine benzoateSphaerophysine benzoate Drastic compoundDrastic compound. . In orange In orange

glass tightly closed containerglass tightly closed container, , in in the place protected from lightthe place protected from lightвв..

Ganglioblockator meanGanglioblockator mean, , uterine muscle stimulantuterine muscle stimulant. . Used Used for the treatment of for the treatment of hypertension and strengthening hypertension and strengthening of maternity activity byof maternity activity by 0,03 0,03gg 2-3 2-3 times per day ortimes per day or ii//mm byby 1 1ml ml ofof 1% 1% solutionsolution..

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 imidazolPilocarpine hydrochloride (Pilocarpini

hydrochloridum)

α-Ethyl-β-(1-methylimidazollyl-5-methyl)-γ-butyrolactone hydrochloride

(3S,4R)-3-Ethyl-4-[1-methyl-1Н-imidazol-5-yl)methyl]dihydro-3Н-furan-2-one hydrochloride

5(3-ethyl-4,5-dihydrofuranone-2)-methylene-1-methylimidazol hydrochloride

N

N CH3

O

C2H5 CH2

O

HCl

Obtaining of pilocarpinePilocarpus 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 hydrochloride1. Substance gives reaction on chlorides.2. 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.

3. 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)

HC

CH

COOHHO

HOOC OH

N

O

C

C CH2

CH2

O

C

CCH

O O

OH

CH3CH3

CH

H3C

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 hydrotartrate1. 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 :

OH C

O

H OH

HO

H2SO4

OH

COH

HO

O

H2SO4

CHOH

HO

OH+ +

-2H2O

-2H2O

àóðè í î âèé áàðâí è ê

Aurine dye-stuff

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)

Derivative of 1,2,3,4 tetrahydroquinolysine-6, condensed with piperidine

White or slightly yellowish crystalline powder. Easily soluble in water, alcohol and chloroform.

N

O

NH

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 cytisine1. 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.

H2N

N

NH

O

N

O

NH

HO

NaOH

HCl

NaNO2

HNO3

N+N

O2N

NaO

N N

N

O

NH

N

NH

O

N NH

O

Cl-

[ H ]

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)

or

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.

N

NHI

N

NCH2 HI

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 hydroiodide1. 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).

3. Alkalimetry in alcohol medium by thymolphthalein в (Е=М.m).

4. Photocolorimetry.

Alkaloids – derivatives of quinoline To this group alkaloids of quinine cortex belong – 24

alkaloids, the main representative of which is quinine:

6'-Methoxyquinoline-(4')-[5-vinylquinuclidine-(2)]-carbinol

3 H2O

N

H3CO

CHHO

N

HC CH2

Quinine sulfate (Chinini sulfas) Quinini sulfas*

neutral salt

Quinine hydrochloride

(Chinini hydrochloridum) Quinini hydrochloridum*

neutral salt

N

CH

HON

HC CH2

H3CO * HCl *2H2O

* H2SO4 * 2H2O

N

H3CO

CHHO

N

HC CH2

Quinine dihydrochloride (Chinini

dihydrochloridum)

Acidic salt

Cinchona (Cinchona Remija)

* 2HCl

N

H3CO

CHHO

N

HC 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 salts1. 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:

N

CH

HON

HC CH2

H3COBr2

N

CH

HON

HC CH2

HN

NH

OH OH

N

CH

HON

HC CH2

O

O

Br Br

NH4OH

Òàëåé î õ³í

Thaleyoquine

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.

N

H3CO

H

R

N

H3CO

H

R

N

H3CO

R

N

H3CO

RO

O

N

H3CO

H

RO

O

5

7

Br2; OH-; K3[Fe(CN)6]

- H2

5

7

R - õ³í óêë ³äè í î âè é ô ðàãì åí ò õ³í ³í ó

Åð³òðî õ³í

R-quinuclidine fragment of quinine

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;

N

CH

HON

HC CH2

H3CO Br2

N

CH

HON

HC CH2

H3CO

Br Br

.

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.treatment of malaria.

Quinine hydrochloride: tabl. 0,25 and 05 g; Quinine dihydrochloride: 50 % solution 1,0 ml

Thank you for attention!