Lecture 2

Alkaloids of tropane,derivatives, ecgonine, isoquinoline. Social

importance of the research to the analgesics such as morphine.

As. Kozachok S.S.

ropane bicyclic condensed system, which contains the piperidine and pirrolidine cycles.
7 1 2

N N H Pyrrolidine N H Piperidine
6 5

CH3 3
4

Tropane

ropane is a base of the alkaloids row and their structural analogs. According to the chemical structure these compounds are divided into two groups: derivatives of tropane alcohol (1) and derivatives of tropane-2- carboxylicecgonine (2):
COOH

N 1

CH3

OH

N 2

CH3

OH

Tropanes alkaloids are in the plants of Solanaceae family (belladonna, datura, hioscyamus niger).

The maine representatives of topanes alkaloids are racemic atropine, its left rotation isomer hyoscyamine and the analogue of hyoscyamine - scopolamine. Atropine was first isolated from belladonna in 1833. In the plants it is contained in very small quantities with hyoscyamine and scopolamine together. Obtaining the atropine and hyoscyamine from plant materials in the form of bases (after treatment with ammonia), organic solvents (dichloromethane, benzene). Atropine is formed from hyoscyamine by racemization at 114-116 C, at a higher temperature is formed apoatropin having no pharmacological activity of atropine. After hyoscyamine separation from solution, scopolamine is released.

Synthetically extracted from amber aldehyde, methylamine, acetone and d, l-tropic acid.

Atropine sulphate (Atropini sulfas) (SPhU)

CH2OH N CH3 O C O
2

CH

C6H5

* H2SO4 * H2O

bis(1R,R,5S)-3-[(RS)-(3-hydroxy-2-phenylpropanoate) oxy]-8-methyl-8-azabicyclo[3.2.1] octane sulfate monohydrate Bis[(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2RS)-3hydroxy-2-phenylpropanoate] sulphate monohydrate. Tropine ester d,l-tropic acid sulfate monohydrate

Scopolamine hydrobromide (Scopolamini hydrobromidum)

CH2OH O N CH3 O C O CH C6H5 * HBr * 3 H2O

Scopolamine ester (-)-tropic acid hydrobromide, trihydrate IUPAC ()-(S)-3-hydroxy-2-phenylpropionic acid(1R,2R,4S,7S,9S)-9-methyl-3-oxa-9azatricyclo[3.3.1.02,4]non-7-yl ester

Physical properties
Atropine sulphate White or almost white, crystalline powder or colourless crystals. Very soluble in water, freely soluble in ethanol (96 per cent). Scopolamine hydrobromide White or almost white, crystalline powder or colourless crystals. Freely soluble in water soluble in ethanol, very slightly soluble in chloroform.

Melting at 190 and decomposing.

Identification
Atropine sulphate 1. According to the physicalchemical constants: infrared spectroscopy and optical rotation (-0,5-+0,05). 2. Melting point of atropine picrate. 3. Vitali's-Morena reaction ( on tropic acid). 4. It gives the reactions of sulphates. 5. It gives the reaction of alkaloids Non pharmacopoeia reaction: ) Melting point of atropine base (115-117 ) after settled down by ammonia solutiobn; b) formation of benzaldehyde (small of bitter almond) at the heating atropine with sulfuric concentrated acid and crystalline potassium dichromate:
1.

2.
3.

4.

Scopolamine hydrobromide It gives the reactions of bromides (three reaction according to SPhU). Vitali's-Morena reaction ( on tropic acid). Melting point (192-196 ) and optical rotation : -22 till -26 (5 %-water solution). It gives the reaction of alkaloids

Formation of benzaldehyde

Vitali's-Morena reaction To about 1 mg add 0.2 ml of fuming nitric acid R and evaporate to dryness in a waterbath, formation a polynitrocompound of a yellow colour. Dissolve the residue in 2 ml of acetone R and add 0.1 ml of a 30 g/l solution of potassium hydroxide R in methanol R. A violet colour develops.

Purity test
Atropine sulphate
1.

Scopolamine hydrobromide
1.

Apoatropine(<0,5%) spectrophotometrically

2.

Outsiders (foring) alkaloids Thin layer chromatography (TLC)

Apoatropine, aposcopolamine and other reducing substances according to the reaction with 0,1 of potassium permanganate the pink colour doesnt develop during 5 minutes. Outsiders (foring) alkaloids are determined by the addition of ammonia solution, after that must be any turbidity observation.

Quantitative determination
Atropine sulphate
Acid-base titration in nonaqueous medium, a direct titration with potentiometric fixing of the equivalent point. (=.). 2) Alkalimetry in ethanolchloroform medium (=./2). 3) Photocolorimetry by the reaction with picric acid.
1)

Scopolamine hydrobromide
1) Acidimetry in

nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator crystal violet (=.). 2) Argentometry by the Faience method in the acetate medium, the indicator - bromophenol blue (=.).

CH2OH CH3COOH N CH3 O C O CH2OH H N+ CH - 3 ClO4 O C O CH C6H5 + H N+ CH - 3 HSO4 O C O CH C6H5 * H2SO4 + HClO4
2

CH2OH CH C6H5

CH2OH CH3COOH 2O N CH3 O C O CH2OH 2 O H N+ CH3 O C O CH C6H5 ClO4- + HgBr2 + 2 CH3COOH CH C6H5 * HBr + Hg(CH3COO)2 + 2 HClO4

Storager, applcation
Atropine sulphate
Protected from light. Anticholinergic (spasmolytic, under the influence of atropine is a strong dilation of the pupils midriatic effect ) medicine. Used to study the eye fundus, at the spasms of smooth muscles, antidote to acetylcholine. Intravenous injection , inner muscular injectio, eye drops. Producing powder, ampoule 0,1% - 1,0. Poisoning substance. H.d..-0,001 g, H.d.d.- 0,003 g. Preparations: Atropine Eye Drops Atropine Eye Ointment Atropine Injection Atropine Tablets Morphine and Atropine Injection

Scopolamine hydrobromide
Protected from light. Anticholinergic . Midriatic effect is not continue. Exhibits a calming effect on the CNS. Treatment of parkinsonism . hypodermic injection, eye drop. Producing - powder, ampoule 0,05% - 1,0. Poisoning substance. H.d.0,0005 g, h.d.d.- 0,0015 g. Scopolamine butylbromide (Spazmobryu, Buscopan, Buskotsin-M)

Synthetic analogues of atropine

Atropine and scopolamine - valuable medicinal compounds, but they often give side effects. In the search for new biologically active compounds of the tropanes rows there were synthesized esters of tropine with almond and diphenylacetate acids homatropine and tropacyn

Homatropine hydrobromide (Homatropini hydrobromidum)

OH N CH3 O C O CH C6H5 * HBr

Tropacyn, Diphenyltropane hydrochloride (Tropacinum)

C6H5 N CH3 O C O CH C6H5 * HCl

Tropine ester of almond acid hydrobromide (N,N-dimethyl-8-azoniabicyclo[3.2.1]oct3-yl) 2-hydroxy-2-phenylacetate bromide

Tropine ester of diphenylacetate acids hydrochloride

-adrenaline receptors agonist, weak anticholinergic. Producing:lyophilized powder for injection.

Tropaphenine (Tropaphenum). Expressed

Troventoline (Troventolum). Bronchodilatory drug. Aerosol. Atrovent ((Ipratropiumbromide ). Bronchodilatory drug. Aerosol.

Obtaiing of synthetic analogs of atropine

According to the interaction between tropine and according acid or its chlorhydride:
O C N CH3 OH Cl CH R2 R1 N CH3 O C O CH R2 R1

Physical properties
Homatropine hydrobromide
White or almost white, crystalline powder. Freely soluble in water, slightly soluble in alcohol, very

Tropacyn
White or almost creamy white crystalline powder. Freely soluble in water, alcohol and chloroform, practically insoluble in ether and benzole.

slightly soluble in chloroform, practically insoluble in ether.

Identification
1. 2. 3.

4.

5.

6. 7.

Homatropine hydrobromide It gives the reactions of bromides (three reaction according to SPhU). It gives the reaction of alkaloids With iodine solution settled down the brown sediment of substance periodide. With solution white sediment, its dissolved in the excess of the reagent. Homatropine base at the heating with mercury (II) chloride alcohol gives yellow colour which transfers into red-orange (unlike from the most of alkaloids, except atropine and hyoscyamine). Hydroxamic reaction . Doesnt give Vitali's-Morena reaction.

Tropacyn
1. Give Vitali's-Morena reaction

2. 3.
4.

5.

(on diphenylacetate acid). Melting point. It gives the reaction of alkaloids It gives the reactions of chlorides (two reaction according to SPhU). Hydroxamic reaction.

Vitali's-Morena reaction on tropacyn:

Quantitative determination
Homatropine hydrobromide
Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator - crystal violet (=.). 2) Alkalimetry in water-alcohol medium at the present in chloroform (=.).
1)

Tropacyn
1) Acidimetry in nonaqueous

medium, a direct titration at the present of mercury (II) acetate, the indicator crystal violet (=.). 2) Tropacyn in tablets is determined argentometric by Folgard method (=.).

Storage, application
Homatropine hydrobromide
Protected from light. Anticholinergic (midriatic) medicine. Using eye drops 0,250,5-1% solutions. Doesnt use at the treatment of glaucoma. Producing - powder, ampoules 0,1% - 1,0. Poisoning substance. H.d.-0,001g, H.d.d.0,003 g. Tropacyn Protected from light. Anticholinergic. Midriatic effect is not continue, actively influence on the central holynoreactive system. Treatment of Parkinson's disease, spasms of smooth muscles of the abdominal cavity, stomach ulcers. Intravenous. Producing - powder, tablets 1, 3, 5, 10, 15 mg. Poisoning substance. H.d.-0,03 H.d.d.- 0,1 g.

Tropanes alkaloids ecgonine types

Cocaine hydrochloride (Cocaini hydrochloridum)
COOCH3

CH3

C O

C6H5 * HCl

Hydrochloride of methyl ester benzoylecgonine Cocaine is methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8methyl-8-azabicyclo[ 3.2.1]octane-2-carboxylate hydrochloride

(Erythroxylon Coca)

May be obtained from the leaves of Erythroxylum coca Lam. and other species of Erythroxylum or by synthesis.

Physical properties Colourless crystals or a white, crystalline powder. Slightly volatile. Very soluble in water; freely soluble in ethanol (96%), soluble in chloroform and glycerinein, practically insoluble in ether. Identification 1. It gives the reactions of chlorides. 2. Melting point (not lell 195 ); optical rotation - from -71 till -73 (2,5 %-water solution); specific absorption rate . 3. Hydroxamic reaction (on the ester group). 4. It gives the reaction of alkaloids

5. With potassium permanganate solution forming the violet crystalline sediment- cocaine permanganate (difference from novocain):

6. If, in an aqueous solution of cocaine to add drop by drops a 5% solution of chromic acid H2CrO4, then from each drop not stable turbidity appears. With further addition of HCl conc. formed an amorphous orange-yellow precipitate.

7. At the heating of cocaine hydrochloride with sulfuric concentrated acid appearance the acidic hydrolysis its products are methyl alcohol, benzoic acid. These products interact with each other to form methyl benzoate, which has a characteristic odor:

At long staing from the reaction mixture crystals of benzoic acid settle down

Purity test

Unacceptable impurity cinnamoylcocaine and other reducing substances with n4 solution it doesnt colourlessed during 30 minutes. Impurity of truxilline and other coca alkaloids are determined by the addition of ammonia solution: if the impurities are not present the cocaine base settles down, if they are present any sediment formation.

Quantitative determination

Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator - crystal violet (=.). Alkalimetry in ethanol-chloroform medium (=.). Iodometry, back titration after precipitation of polyiodide cocaine C17H21NO4HJJ2 (=../2).

Storage
Protected from light.

Action and use

Local anaesthetic. Used as a surface anesthetic for anesthesia of the cornea (1-3% solution) and the mucous membranes of the nose, throat, urinary tract (2-5% solution). Has a marked effect on the CNS, can cause euphoria, excitement, and then CNS depression (addictive - cocainism). Because the drug is toxic and quite deficient, synthesized series of its substitutes (benzocaine, procaine, trimekain, lidocaine), with account relationship between structure and action local anaesthetic drugs. Producing powder, ampoules 2%-1,0. Poisoning substance. H.d.- 0,03 g, h.d.d.- 0,03 g.

Alkaloid isoqinoline derivatives

From the many alkaloids, isoquinoline derivatives in medicine is mainly used as two groups of drugs: derivatives of 1benzylisoquinoline and morphinan (phenantrenisoquinoline).

The source of the 1-benzylisoquinoline and morphinan of the alkaloids derivatives are opium - the milky juice of the immature fruits soporific poppy (Papaver somniferum). The composition of opium (20-25%) is more than 20 alkaloids (morphine, narcotine, papaverine, codeine, thebaine, etc.). Alkaloids found in opium in the form of salts of meconate ( -oxy- -pyrone- -dicarboxylic), lactic and sulfuric acids. Narcotine and papaverine as a very weak basis are in a free state.

The separation scheme of main opium alkaloids by the method of Kanevska-Klyachkina Opium 4-th tymes extraction by water at 50-55 0C
The remainders from the extraction Water extract contains ballast substances, a little papaverine, (concentrated in vacuum at and 2/3 half of all narcotine. Alkaloids are 0C add ammine and ethanol 60-70 extracted by the dichloroethane Filtrate Sediment contains morphine, narcotine, meconate acidified by an acetic acid at the ammonium which are not soluble in alcohol present of sodium acetate and Dichloroethane extract extracted by dichloroethane Contains papaverine which is like a very weak Water solution base doesnt form with acetatic acid at the contains codeine, thebaine and present of sodium acetate, salt. Remove the solvent from the extract other alkaloids which are formed Papaverine with acetic acid water solubility is purified according to the formation of a acetates at the present of sodium hard soluble salt

acetate

The precipitate obtained by the mixing of an aqueous extract of opium with an alcoholic solution of ammonia, processed according to the scheme: The precipitate is heated with the diluted alcohol at 70 0C and filtrated The precipitate The filtrate is extracted by an acetic acid. Narcotine as a very weak base doesnt form the salt. And it is in sediment. Filtrate
Narcotine sediment is purified by a crystalisation from an alcohol or acetone
contains morphine acetate to add ammine and to filtrate Morphine is purified by a crystalisation from a diluted hydrochloric asid solution

contains meconate ammonium

meconate acid

Alkaloids of 1-benzylisoquinoline derivatives

Papaverine hydrochloride (Papaverini hydrochloridum)
H3CO
5 6 4 3

Drotaverine hydrochloride (Drotaverini hydrochloridum) N-Shpa (Nospanum)

C2H5O
5 6 4 3

H3CO H3CO

7 8 21 3
1

N
2 1

C2H5O C2H5O

7 8 21 31 11
1

NH
2 1

11
1

CH2 * HCl

CH * HCl
61 51

H3CO 51 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy isoquinolinehydrochloride

61

C2H5O

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy1,2,3,4-tetrahydro- isoquinoline hydrochloride

Physical properties Papaverine hydrochloride (SPhU) White or almost white crystalline powder or white or almost white crystals. Sparingly soluble in water, slightly soluble in alcohol. It can fuse with KOH (forming dimethoxyisoquinoline and dimethoxytoluol) and oxidized by MnO4 (oxidation products are pyridine- threecarbonic acid and 3,4-dimethoxybenzoate (veratic) acid). It has reducing property according to the two aromatic fragments bounding by methylene group, as well as a four methoxide groups. Drotaverine hydrochloride Yellow crystalline powder. Soluble in water and ethanol, not soluble in an ether.

Identification of Papaverine hydrochloride 1. Determination of specific absorption by UV spectroscopy. 2. Melting point of a papaverine base after it is settled down by ammonia. To 10 ml of solution S (see Tests) add 5 ml of ammonia R dropwise and allow to stand for 10 min. The precipitate, washed and dried, melts (at 146 C to 149 C. 3. Karolinovs test : after the heating of the substance with acetic anhydride and sulphuric acid solution is pained in an yellow colour with a green fluorescence. 4. It gives reaction of chlorides. 5. Nonpharmacopoeia reactions: ) with a concentrated sulphuric acid the substance at the heating is coloured in violet; b) at mixing ethanols solutions of papaverine and iodine a darkred crystals of the hydroiodide diiodopapaverine C29H19O4NJ2HJ settle down;

c) It gives the reaction of alkaloids ; d) With nitric acid forming an yellow colour that transfers into orange at the heating;
H3CO H3CO H3CO N H3CO CH2 HNO3 H3CO CH2 N HNO3 t C
0

N H3CO O2N CH2

NO2

NO2

H3CO

OCH3

H3CO

OCH3

H3CO

OCH3

e) With bromine water papaverine forms an yellow sediment brompapaverine hydrobromide

f)

With Marki reagent at the first step forming a red colour than yellow and bright-orange. Formed methylendipapaverine with bromine water and ammine gives a violet sediment, which is dissolved in an

alcohol and gives violet-red colour.

H3CO OCH3 OCH3 OCH3

H3CO

C H2 C H2 C H2

OCH3
2OCH3 SO4

H3CO

N+ H

N+ H

Drotaverine hydrochloride
Drotaverines molecule is considered as the condensation product of 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline and 3,4Dimethoxybenzaldehide. The drug has a characteristic absorption spectrum in the UV region Drotaverine has more basic properties than papaverine, therefore, for the extraction of the basics from the medicine solution you need to add alkaline solution. As well as papaverine, drotaverine has a reducing properties. When added to a sample of the drug a conc. H2SO4 and added followed by drop a diluted HNO3 appearance a dark brown colour.

Quantitative determination of papaverine

hydrochloride
Alkalimetry in a mixture medium of an alcohol and 0,01 chloric acid with potentiometric fixing of the equivalent point. (=.). Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator - crystal violet (=.). Alkalimetry in a water-alcohol medium without chloroform, cause papaverine is a very weak base

(=.).

Argentometric by Folgard method. Spectrophotometry (in dosage forms) (=.). Quantitative determination of a drotaverine hydrochloride by the same methods as a papaverine hydrochloride.

Storage, application
Papaverine hydrochloride
Protected from light Phosphodiesterase inhibitor; smooth muscle relaxant. Using per oral 40-80 mg 3-4 times a day, parenteral 1-2 ml of 2% solution. Producing - powder, tablets 40 mg, ampoules 2% - 2,0, suppositories 0,2 g. Strong action stuff. Included in the tablets of Papazol, andypal, Nicoverine.

Drotaverine hydrochloride
Protected from light. smooth muscle relaxant. Using per oral 40-80 mg 2-3 times a day, inject i/m 2-4 ml of 2% solution. Producing - tablets 40 mg, ampoules 2% - 2,0. Strong action stuff. Included in the tablets of Nishpan (with nicotinic acid), Bishpan (with isopropamide)

Alkaloid of morphinan derivatives

The main alkaloid of opium is morphine, it is the derivatives of morphinan:

Morphinan

Morphine: 3,6-dioxy-N-methyl-

4,5-epoxymorphinen-7;

In the molecule of morphine are 5 asymmetric carbon atoms. High reactivity of oxygroups, yields to obtain a large number of its semisynthetic derivatives:

Morphine hydrochloride (Morphini hydrochloridum)

HO

* HCl * 3 H2O N CH3

HO

Three hydrate hydrochloride 3,6-dioxy-4,5-epoxy-17 methylmorphinen-7 7,8-Didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol hydrochloride trihydrate.

Physical and chemical properties of Morphine

White needle-shaped crystals or white crystalline powder, slightly yellow during storage. Slowly soluble in water, difficult soluble in alcohol, very slightly soluble in chloroform and ether. Acid-base properties are explained by the presence of a tertiary nitrogen atom (the center core) and phenolic hydroxyl (center of acidity). The basic properties of morphine are less expresed than in ammonia, and acidic is somewhat stronger than in phenol . Pronounced reducing properties are dued to the affiliation of morphine to a partially hydrogenated phenanthrene system, as well as the presence of phenolic hydroxyl and the secondary alcohol group.

Identification of Morphine hydrochloride

1.

2. 3.

4. 5. 6.

Optical rotation from -97 till -99 (2 % water solution). Appearance of the 5 asymmetric carbon atoms (5, 6, 9, 13, 14) gives an optical activity for a substance. It gives reaction of chlorides. When to added an ammonia to a solution of a substance releasing a white crystalline precipitate which is dissolved in a solution of sodium hydroxide (according to the formation of sodiums salt due to the presence of phenolic hydroxyl). It gives the reaction of alkaloids With Phrede reagent morphine gives a violet color, passing into blue, at a staying - in green. With Marki reagent appearance a purple coloration, rapidly transforms into a blue-violet (unlike from codeine).

7. Oxidation of morphine by Mandelina reagent (a solution

of ammonium vanadate in the conc. H2SO4) leads to the formation of the purple product. 8. With Erdman reagent forming a red product.

9.

Pellagry reaction. At the action of a concentrated H2SO4 or a concentrated HCl forming apomorphine, which from the addition of a concentrated HNO3 becomes intense red color. If apomorphine is dissolved in water, which is neutralized by Na2CO3 and to add 1-3 drops of iodine solution, then appearance a green color. If the green solution shake with ether, the ethereal layer is painted in red and water remains green. 17H19O3N C17H17O2N + H2O
morphine apomorphine

10. With a concentrated HNO3 formig an intramolecular chelate of

orange-red color.

11. The oxidizing by a potassium hexacyanoferrate (III)

in acidic medium with forming oxydimorphine. At the further addition of iron (III) chloride to the prepared solution it is formed "Prussian blue" (dark blue color):

12. With a solution of iron (III) chloride appearance a blue coloration

(reaction to the phenolic hydroxyl), which quickly disappears according to the oxidation of morphine by the reagent. 13. Halogenation (reaction to a phenolic hydroxyl). 14. With diazoniums salts it is formed an azo dye (due to the presence of phenolic hydroxyl).

15. The Oxidation of the secondary alcoholic hydroxyl to a ketone with a subsequent formation of an oximes, hydrazones, semicarbazone 16. Esterification goves either a phenolic or the secondary alcoholic hydroxyl group.

17. Morphine, just like other phenols, easily is oxidized. Since the

interaction with HJO3 it releases a free iodine. Alkaline solutions of morphine are very easy oxidized and form oxydimorphine (dihydromorphine, psevdomorphine, oxyimorphine):

Quantitative determination of Morphine hydrochloride

Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator - crystal violet (=.). Argentometric by Folgard method ( = ..). Alkalimetry in ethanol-chloroform medium (=.).

Storager, application of morphine Protected from light. Opioid receptor agonist; analgesic. Strong analgesic action. It has an antishock action at traumas, in bigger doses has a hypnotic effect. It is used in the preparation and after surgery, at traumas, cancers. Take per oral 10-20 mg in powder form, or in hypodermic injection - 1% -1.0. Morphinomania is a passion to morphine using. Morphilongis a 0, 5% solution of morphine hydrochloride in 30% aqueous solution of polivinylpyrrolidone. Omnopon is a mixture of hydrochlorides of opium alkaloids (up to 50% morphine, etc.). Naltrexone hydrochloridel, nalorfin and Naloxone (SPhU) are the antidotes to morphine, opiate receptor antagonists.

Codeine medicines
Codeine (Codeinum) (SPhU)
H3CO

Codeine phosphate (Codeini phosphas)

H3CO

* H 2O
O

* H3PO4 * 1,5 H2O N CH3

CH3

HO

HO

4,5-epoxy-3-methoxy-17-methyl-7,8Didehydro-morphinan-6-l; 7,8-Didehydro-4,5a-epoxy-3-methoxy17-methylmorphinan-6a-ol.

Phosphate 3-methoxy-6-oxy-4,5epoxyepoxy-17-methylmorphinan-7; 7,8-Didehydro-4,5a-epoxy-3-methoxy-17methylmorphinan-6a-ol phosphate hemihydrate.

Physical properties
Codeine
White or almost white, crystalline powder or colourless crystals. Solubility Soluble in boiling water, freely soluble in ethanol (96 per cent). It has the strongest basic properties among all alkaloids ( codeine water solution 9,0).

Codeine phosphate
White or almost white, crystalline powder or small, colourless crystals. Solubility Freely soluble in water, slightly soluble or very slightly soluble in ethanol (96 per cent).

Identification of Codeine medicines

1-3. Melting point, compare The IR spectra of the

pharmacopoeia sample and determine the maximal absorption peaks by UV spectroscopy. 4. It gives the reaction of alkaloids
5. At the heated with concentrated sulfuric acid and a solution of
iron (III) chloride appearance a blue color (due to the formation of apomorphine containing phenolic hydroxide).

According to the apomorphine formation codeine gives positive Pellagry reaction (look morphine).

6.

Non pharmacopoeia reaction:

) With Marki reagent appearance blue-violet color

b) with a concentrated nitric acid appearance an orange color, which transfers to yellow. c) With Phrede reagent violet color; d) With Erdman reagent red. ) The esterification of the secondary alcoholic hydroxy.

Identification of Codeine phosphate:

) By the reaction of the detection of phosphate ion with a solution
of Silver nitrate on the formation of yellow precipitate.

PO43- + 3Ag+ Ag 3 PO4 b) on phosphate ion with molybdenvanadium reagent appearance yellow color; PO43- + HVO3 + 11H2MoO4 + 4NH4+ (NH4)4[PO4(MoO3)11VO3] + 11H2O + H+ c) Melting point of codeine base, precipitated by sodium hydroxide (154-157 ).

Quantitative determination
Codeine medicines
Codeine Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator crystal violet (=.). Codeine as a strong base is determined by alkalimetry in water-alcohol medium, the indicator methyl red ( =
..).

Codeine phosphate Acidimetry in nonaqueous medium( = ..). Alkalimetry in chloroformalcohol medium, idicator phenolphthalein ( = ../2).

Storager, applcation of Codeine

Protected from light. Opioid receptor agonist; analgesic. Antitussive, mild analgesic effect. It is included in the tablets of Kodterpine (terpinehydrate, sodium bicarbonate), Tablets from cough, Pentalgin, sedalgin Solpadein, Behterrov tincture (sodium bromide, tincture adonis). Release form powder, tablets. H.d.-0, 05 g; H.d.d.-0, 2 g. Codeine phosphate as a less toxic (80% codeine base) can be taken in higher doses for children. Produsing powder. H.d - 0, 1 g; H.d.d.-0, 3 g.

Ethylmorphine hydrochloride (Aethylmorphini hydrochloridum) Dionine (Dioninum)

C2H5O

Properties Crystalline powder of white or nearly white. HCl * 2 H2O Soluble in water and N CH3 96% alcohol, practically insoluble in ether.

HO

(5R, 6S) 4,5-epoxy-3ethoxy-N-methylmorphine7-n-6-ol hydrochloride

Identification of Ethylmorphine
hydrochloride
IR spectra. Melting point of ethyl morphine base, precipitated by sodium hydroxide. At the heating a substance with a concentrated H2SO4 and a solution of FeCl3 appearance a blue color (formation of apomorphine), goes into the red after the addition of a concentrated nitric acid (Pellagry reaction). It gives the reaction of chlorides.

Non pharmacopoeia reaction:

) Iodoformic test. At the heating of a mixtuer of substance, crystalline iodine and sodium hydroxide till boiling point, appearance characteristic odor of iodoform:

b) 3 With a concentrated nitric acid appearance an orange color. c) UV spectroscopy .

Quantitative determination
1)

Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator crystal violet (=.). Alkalimetry in water-alcohol medium with addition of chloroform ( = ..). Storager Protection from light

Application
Analgesic (narcotic), and antitussive medicine. For the treatment of the eye as anti-inflammatory agent (1-2% drops or ointment). Powder, tab. at 0.01 and 0.015 g, the H.d. - 0,03 g; H.d.d. - 0,1 g.

Synthetic analogue of morphine on the pharmacological action. One of the first in this series have been synthesized promedol, and more recently - tramadol.

Other narcotic analgesics Pentasocyn (Fortran) - Tables, amp, a strong analgesic, less respiratory depression, rarely observed phenomenon of addiction and withdrawal. Buprenorphine h/chl (SPhU) - Tables. to 0.2 mg. Butorphanol hydrotartratis (Beforal, moradol) containes in a car kits. Promedol - table, amp, syringe-tube, a strong analgesic for labor analgesia. Fentanyl - amp, for sedation. Tramadol (Tramal) - Capps, amp, suppositories. Ketorolac (Ketanov, Ketorol, Ketolonga-Darnitsa, etc.) analgesic effect equated to morphine is not addictive, Table, amp. Ketoprofen (ketonal, F-gel, gel Fastum) - Tables, tabl.retard, capsules, suppositories, amp, gel, cream)

Alkaloids of apomorphine derivateves

4 5 3

(Apomorphini hydrochloridum)
2 1

HO

7 8 9 10

CH3

HO * HCl * 3/4 H2O N CH3

5,6 dioxyapomorphine

Glaucine hydrochloride (Glaucini hydrochloridum) Glauvent

Alkaloid from the herba of Glaucii Flavi
OCH3 H3CO

* HCl H3CO N CH3

H3CO

4,5,7,8tetramethoxyapomorphine hydrochloride

1.
2. 3.

4.

5. 6. 7.

Identification of apomorphine hydrochloride It gives the reaction of chlorides. With HNO3 conc. blood-red color. Alkali solution extract from the substance solution a free apomorphine as a white precipitate which is dissolved in excess of alkali (due to the formation of sodium salt due to the presence of phenolic hydroxyl). Oxidation reaction (Pellagry ): with iodine solution in the presence of NaHCO3 and ether - the ether layer is painted in red-violet color, and water becomes green. Optical rotation from -46 till -52 (in HCl solution). With Marki reagent violet color which transfers in green. Vitali's-Morena reaction.

Quantitative determination
1) Acidimetry in nonaqueous medium, a direct titration at the

present of mercury (II) acetate, the indicator - crystal violet (=.). Storager Protected from light Applcation Apomorphine hydrochloride emetic, expectorant. At poisoning it is used of 0,2-0,5 ml solution of 1% hypodermic injection. Expectorant action - 5.1 mg orally. Glaucine hydrochloride antitussive medicine, unlike as codeine does not suppress breathing, non-addictive, shows a moderate hypotensive effect. Table. By 0,05 g.

Thanks for attention