LectureLecture №24 №24Alkaloids derivatives of Alkaloids derivatives of tropanetropane, , ecgonineecgonine and isoquinoline. Social and isoquinoline. Social
significance of the research which help significance of the research which help to find the morphine-type analgesicsto find the morphine-type analgesics
As. Kozachok S.SAs. Kozachok S.S..
Тropane – bicyclic condensed system, which contains the piperidine and
pirrolidine cycles.
NH
NH
N CH3
1 2
3
456
7
Ï ³ðî ë ³äè í Ï ³ï åðèäè í Òðî ï àíPyrrolidine Piperidine Tropane
Тropane 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- carboxylic–ecgonine (2):
N CH3 OH N CH3
COOH
OH
1 2
Tropane’s alkaloids are in the plants of Tropane’s alkaloids are in the plants of Solanaceae familySolanaceae family (belladonna, datura, (belladonna, datura,
hioscyamus niger).hioscyamus niger).
The maine representatives of topane’s alkaloids are The maine representatives of topane’s alkaloids are racemic racemic atropine, its left rotation isomer – hyoscyamine and the analogue of atropine, its left rotation isomer – hyoscyamine and the analogue of hyoscyamine - scopolamine.hyoscyamine - scopolamine.
Atropine was first isolated from belladonna in 1833. In the plants Atropine was first isolated from belladonna in 1833. In the plants it is contained in very small quantities with hyoscyamine and it is contained in very small quantities with hyoscyamine and scopolamine together.scopolamine together.
Obtaining the atropine and hyoscyamine from plant materials Obtaining the atropine and hyoscyamine from plant materials in the form of bases (after treatment with ammonia), organic solvents in the form of bases (after treatment with ammonia), organic solvents (dichloromethane, benzene). Atropine is formed from hyoscyamine (dichloromethane, benzene). Atropine is formed from hyoscyamine by racemization at 114-116 ° C, at a higher temperature is formed by racemization at 114-116 ° C, at a higher temperature is formed apoatropinapoatropin having no pharmacological activity of having no pharmacological activity of atropineatropine. After . After hyoscyamine separation from solution, scopolamine is released.hyoscyamine separation from solution, scopolamine is released.
Synthetically extracted from amber aldehyde, methylamine, acetone and d, l-tropic acid.
Atropine sulphate (Atropini sulfas) (SPhU)
bis(1R,ЗR,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)-3-hydroxy-2-phenylpropano] sulphate monohydrate.
Tropine ester d,l-tropic acid sulfate monohydrate
N CH3 O C CH
CH2OH
C6H5
O
* H2SO4 * H2O
2
Scopolamine hydrobromide (Scopolamini hydrobromidum)
Scopolamine ester (-)-tropic acid hydrobromide, trihydrate IUPAC
(–)-(S)-3-hydroxy-2-phenylpropionic acid(1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester
N CH3 O C CH
CH2OH
C6H5
O
O * HBr * 3 H2O
Physical propertiesPhysical properties
Atropine sulphateAtropine sulphate
White or almost white, crystalline powder or colourless crystals. Very soluble in water, freely soluble in ethanol (96 per cent).
Melting atMelting at 190°С 190°С and and decomposing.decomposing.
Scopolamine Scopolamine hydrobromidehydrobromide
White or almost white, crystalline powder or colourless crystals. . Freely soluble in water in water soluble in ethanolin ethanol, , very very slightly solubleslightly soluble in in chloroformchloroform..
IdentificationIdentificationAtropine sulphateAtropine sulphate
1.1. According to the physical-According to the physical-chemical constantschemical constants: infrared : infrared spectroscopyspectroscopy andand ooptical rotation (-0,5(-0,5оо-+0,05-+0,05оо).).
2.2. Melting point of atropine picrateMelting point of atropine picrate..3.3. Vitali's-Morena reaction ( Vitali's-Morena reaction ( on on
tropic acidtropic acid). ). 4. It gives the reactions of sulphates..5. It gives the reaction of alkaloids
Non pharmacopoeia reaction: : а) а) Melting point of atropine baseMelting point of atropine base
(115-117 °С) (115-117 °С) after settled down after settled down by ammonia solutiobnby ammonia solutiobn;;
bb) ) formation of benzaldehyde formation of benzaldehyde ((small small of bitter almondof bitter almond)) at the heating at the heating atropine with sulfuric atropine with sulfuric concentrated acid and crystalline concentrated acid and crystalline potassium dichromatepotassium dichromate::
Scopolamine hydrobromideScopolamine hydrobromide1. It gives the reactions of
bromides ((three reaction three reaction according to SPhUaccording to SPhU).).
2.2. Vitali's-Morena reaction ( Vitali's-Morena reaction ( on on tropic acidtropic acid). ).
3.3. Melting pointMelting point (192-196 °С) (192-196 °С) andand ooptical rotation : -22° : -22° tilltill -26° -26° (5 %-(5 %-water solutionwater solution).).
4. It gives the reaction of alkaloids
Formation of benzaldehyde
Vitali's-Morena reaction 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 testPurity test Atropine sulphateAtropine sulphate
1. Apoatropine(<0,5%)-визначають spectrophotometrically
Outsiders (foring) alkaloids
Thin layer chromatography (TLC)
Scopolamine Scopolamine hydrobromidehydrobromide
1. Apoatropine, , aposcopolamineaposcopolamine and other and other reducing substances reducing substances according to the reaction with according to the reaction with 0,1 0,1 М М of potassium of potassium permanganatepermanganate – – the pink the pink colour doesn’t colour doesn’t develop during during 5 5 minutesminutes..
2. Outsiders (foring) alkaloids are determined by the addition are determined by the addition of ammonia solution, after that of ammonia solution, after that must be any turbidity must be any turbidity observationobservation..
Quantitative determinationQuantitative determinationAtropine sulphateAtropine sulphate
1)1) Acid-base titration in Acid-base titration in nonaqueous mediumnonaqueous medium, , a direct a direct titrationtitration with with potentiometricpotentiometric fixing of the equivalent pointfixing of the equivalent point. . (Е=М.м).(Е=М.м).
2)2) Alkalimetry in Alkalimetry in ethanol-chloroform medium (Е=М.м/2).(Е=М.м/2).
3)3) Photocolorimetry by the Photocolorimetry by the reaction with picric acid.reaction with picric acid.
Scopolamine Scopolamine hydrobromidehydrobromide
1) Acidimetry in in nonaqueous mediumnonaqueous medium, a a direct titrationdirect titration at the at the present of mercurypresent of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
2) Argentometry by the Faience method in the acetate medium, the indicator - bromophenol blue (Е=М.м).(Е=М.м).
N CH3 O C CH
CH2OH
C6H5
O
CH3COOH
N+ CH3 O C CH
CH2OH
C6H5
O
H N+ CH3 O C CH
CH2OH
C6H5
O
HClO4
- HSO4-
* H2SO4
2
+ HClO4
+
N CH3 O C CH
CH2OH
C6H5
O
OCH3COOH
N+ CH3 O C CH
CH2OH
C6H5
O
HO
* HBr + Hg(CH3COO)2 + 2 HClO4
+ HgBr2 + 2 CH3COOH2
2
ClO4-
StoragerStorager, , applcationapplcationAtropine sulphateAtropine sulphate
Protected from light. Anticholinergic ((spasmolytic, spasmolytic,
under the influence of atropine is a under the influence of atropine is a strong dilation of the pupils - strong dilation of the pupils - midriatic effectmidriatic effect ) ) medicinemedicine. . Used to Used to study the eye fundus, at the study the eye fundus, at the spasms of smooth muscles, spasms of smooth muscles, antidote to acetylcholine.antidote to acetylcholine.
Intravenous injectionIntravenous injection , , iinner muscular nner muscular injectioinjectio, , eye dropseye drops. . ProducingProducing - - powderpowder, , ampouleampoule 0,1% - 1,0. 0,1% - 1,0. PPoisoningoisoning substancesubstance. . HH..dd..-0,001 ..-0,001 gg, , HH..dd..dd.- 0,003 .- 0,003 gg..
Preparations:Atropine Eye DropsAtropine Eye OintmentAtropine InjectionAtropine TabletsMorphine and Atropine Injection
Scopolamine Scopolamine hydrobromidehydrobromide
Protected from light. Anticholinergic . . Midriatic effect is Midriatic effect is
not continuenot continue. . Exhibits a calming Exhibits a calming effect on the CNS. Treatment of effect on the CNS. Treatment of parkinsonismparkinsonism . .
hypodermic injectionhypodermic injection, , eye dropeye drop. . ProducingProducing - - powderpowder, , ampouleampoule 0,05% 0,05% - 1,0. - 1,0. PPoisoningoisoning substancesubstance. . HH..dd.-.-0,0005 0,0005 gg, , hh..dd..dd.- 0,0015 .- 0,0015 gg..
Scopolamine butylbromide Scopolamine butylbromide (Spazmobryu, Buscopan, (Spazmobryu, Buscopan, Buskotsin-M)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 tropane’s rows there were synthesized esters of tropine with almond and diphenylacetate acids -
homatropine and tropacyn Homatropine hydrobromide
(Homatropini hydrobromidum)
Tropine ester of almond acid hydrobromide
(N-methyl-8-azoniabicyclo[3.2.1]oct-3-yl) 2-hydroxy-2-phenylacetate bromide
Tropacyn, Diphenyltropane hydrochloride (Tropacinum)
Tropine ester of diphenylacetate acids hydrochloride
N CH3 O C CH
OH
C6H5
O
* HBr
N CH3 O C CH
C6H5
C6H5
O
* HCl
Tropaphenine (Tropaphenum). Expressed α-adrenaline receptors agonist, weak anticholinergic.
Producing:lyophilized powder for injection.
Troventoline (Troventolum). Bronchodilatory drug. Aerosol.
Atrovent ((Ipratropiumbromide ). Bronchodilatory drug. Aerosol.
Obtaiing of syntheticanalogs of atropine
According to the interaction between tropine and according acid or its
chlorhydride:
N CH3 OH
C CH
Cl
O
R2
R1
N CH3 O C
O
CHR2
R1
Physical propertiesPhysical properties
Homatropine hydrobromide
White or almost white, crystalline powder. . Freely soluble in water, slightly soluble in alcohol, , very very slightly soluble in slightly soluble in chloroformchloroform, , practically practically
insoluble in etherinsoluble in ether..
Tropacyn
White or almost creamy White or almost creamy white crystalline white crystalline powder. powder. Freely soluble in water, , alcohol and and chloroformchloroform, , practically practically insoluble in ether and insoluble in ether and benzolebenzole..
IdentificationIdentificationHomatropine hydrobromide
1. It gives the reactions of bromides ((three reaction according to SPhUthree reaction according to SPhU).).
2. It gives the reaction of alkaloids 3.3. With iodine solution settled down With iodine solution settled down
the brown sediment of substance the brown sediment of substance periodideperiodide..
4.4. WithWith КОН КОН solution solution – –white white sedimentsediment, , it’s dissolved in the it’s dissolved in the excess of the reagentexcess of the reagent..
5. Homatropine base at the heating base at the heating with mercury (II) chloride alcohol with mercury (II) chloride alcohol gives yellow colour which transfers gives yellow colour which transfers into red-orange into red-orange ((uunlike from the nlike from the most of alkaloids, except atropine most of alkaloids, except atropine and hyoscyamine).and hyoscyamine).
6.6. Hydroxamic reactionHydroxamic reaction ..7.7. Doesn’t give Doesn’t give Vitali's-Morena Vitali's-Morena
reaction.reaction.
Tropacyn
1.1. Give Give Vitali's-Morena reactionVitali's-Morena reaction ((onon diphenylacetate aciddiphenylacetate acid).).
2.2. Melting pointMelting point..3.3. It gives the reaction of
alkaloids4. It gives the reactions of
chlorides ((two reaction two reaction according to SPhUaccording to SPhU). ).
5.5. Hydroxamic reaction.Hydroxamic reaction.
Vitali's-Morena reactionVitali's-Morena reaction on tropacyn:
Quantitative determinationQuantitative determinationHomatropine hydrobromide
1)1) Acidimetry in nonaqueous in nonaqueous mediummedium, , a direct titrationa direct titration at at the present of mercurythe present of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
2)2) Alkalimetry inAlkalimetry in waterwater--alcoholalcohol medium at the present in medium at the present in chloroformchloroform (Е=М.м). (Е=М.м).
Tropacyn
1) Acidimetry in nonaqueous in nonaqueous mediummedium, , a direct titrationa direct titration at the present of mercuryat the present of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
2)2) Tropacyn in tabletsTropacyn in tablets is is determined determined argentometric argentometric by Folgard’ methodby Folgard’ method (Е=М.м).(Е=М.м).
StorageStorage, , applicationapplicationHomatropine hydrobromide
Protected from light..
Anticholinergic ((midriaticmidriatic) ) medicinemedicine. . Using eye drops Using eye drops 0,25-0,25-0,5-1% 0,5-1% solutionssolutions. . Doesn’t use at Doesn’t use at the treatment of glaucomathe treatment of glaucoma. .
ProducingProducing - - powderpowder, , ampoulesampoules 0,1% - 1,0. 0,1% - 1,0. PPoisoningoisoning substancesubstance. . HH..dd.-0,001.-0,001gg, , HH..dd..dd.- .- 0,003 0,003 gg..
Tropacyn
Protected from light..
Anticholinergic. MMidriatic effect idriatic effect is not continueis not continue,,
actively influence on the central actively influence on the central holynoreactive system. holynoreactive system.
Treatment of Parkinson's Treatment of Parkinson's disease, spasms of smooth disease, spasms of smooth muscles of the abdominal muscles of the abdominal
cavity, stomach ulcers.cavity, stomach ulcers.
IntravenousIntravenous. . ProducingProducing - - powderpowder, , tabletstablets 1, 3, 5, 10, 15 1, 3, 5, 10, 15 mgmg. .
PPoisoningoisoning substancesubstance. . HH..dd.-0,03 .-0,03 HH..dd..dd.- 0,1 .- 0,1 gg..
Tropane’s alkaloids ecgonine types
Cocaine hydrochloride (Cocaini hydrochloridum)
Hydrochloride of methyl ester benzoylecgonine• Cocaine is methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-
methyl-8-azabicyclo[ 3.2.1]octane-2-carboxylate hydrochloride
N CH3 O C C6H5
O
COOCH3
* HCl
(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.
Identification1. It gives the reactions of chlorides.2. Melting point (not lell 195 °С); 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 l Unacceptable impurity cinnamoylcocaine and other reducing
substances – with КМnО4 solution it doesn’t 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 (Е=М.м).
• Alkalimetry in ethanol-chloroform medium (Е=М.м).• Iodometry, back titration after precipitation of polyiodide
cocaine C17H21NO4•HJ•J2 (Е=М.м./2).
StorageProtected from light.
Action and useLocal 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.
AlkaloidAlkaloid – – isoqinoline derivativesisoqinoline derivatives From the many alkaloids, isoquinoline derivatives in medicine is
mainly used as two groups of drugs: derivatives of 1-benzylisoquinoline and morphinan (phenantrenisoquinoline).
The source of the 1-benzylisoquinoline and 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 The separation scheme of main opium alkaloids by the method of Kanevska-KlyachkinaKanevska-Klyachkina
Opium4-th tymes extraction by water at 50-55 0C
The remainders from the extractioncontains ballast substances, a little papaverine, and 2/3 half of all narcotine. Alkaloids are extracted by the dichloroethane
Sedimentcontains morphine, narcotine, meconate ammonium which are not soluble in alcohol
Dichloroethane extractContains papaverine which is like a very weak base doesn’t form with acetatic acid at the present of sodium acetate, salt. Remove the solvent from the extract
Papaverineis purified according to the formation of a hard soluble salt
Water extract(concentrated in vacuum at
60-70 0C add ammine and ethanolFiltrate
acidified by an acetic acid at the present of sodium acetate and extracted by dichloroethane
Water solutioncontains codeine, thebaine and
other alkaloids which are formed with acetic acid water solubility acetates at the present of sodium
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 filtrate
contains meconate ammonium
The precipitate
is extracted by an acetic acid. Narcotine as a very weak base doesn’t form the salt. And it is in sediment.
Narcotine sediment
is purified by a crystalisation from an alcohol or acetone
Filtratecontains morphine acetate to add ammine and to filtrate
Morphineis purified by a crystalisation from a diluted hydrochloric asid solution
meconate acid
Alkaloids of 1-benzylisoquinoline derivativesPapaverine hydrochloride
(Papaverini hydrochloridum)
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy isoquinolinehydrochloride
Drotaverine hydrochloride(Drotaverini hydrochloridum)
NО-Shpa (Nospanum)
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-
1,2,3,4-tetrahydro- isoquinoline hydrochloride
N
H3CO
H3CO
CH2H3CO
H3CO
* HCl
12
3
456
78
11
21
31
41
51
61
NH
C2H5O
C2H5O
CHC2H5O
C2H5O
* HCl
12
3
456
78
11
21
31
41
51
61
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 КMnO4 (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 hydrochloride1. 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. Karolinov’s 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:а) with a concentrated sulphuric acid the substance at the heating is
coloured in violet;b) at mixing ethanol’s solutions of papaverine and iodine a dark-
red crystals of the hydroiodide diiodopapaverine C29H19O4NJ2•HJ settle down;
c) It gives the reaction of alkaloids ;d) With nitric acid forming an yellow colour that
transfers into orange at the heating;
e) With bromine water papaverine forms an yellow sediment brompapaverine hydrobromide
N
H3CO
H3CO
CH2
H3CO OCH3
HNO3
N
H3CO
H3CO
CH2
H3CO OCH3
NO2
O2N
N
H3CO
H3CO
CH2
H3CO OCH3
NO2
HNO3
жовте забарвлення оранжеве забарвлення
t 0C
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.
CH2
N+ N+
CH2
CH2
H H
H3CO
H3CO OCH3
OCH3
OCH3H3COOCH3OCH3
SO42-
Drotaverine hydrochloride Drotaverine’s molecule is considered as the
condensation product of 6,7-dimethoxy-1,2,3,4-tetrahydro- isoquinoline and 3,4-Dimethoxybenzaldehide. 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 0,01М chloric acid with potentiometric fixing of the equivalent point. (Е=М.м).
• Acidimetry in nonaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator - crystal violet (Е=М.м).
• Alkalimetry in a water-alcohol medium without chloroform, cause papaverine is a very weak base (Е=М.м).
• Argentometric by Folgard’ method.• Spectrophotometry (in dosage forms) (Е=М.м).• 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)
AlkaloidAlkaloid of of morphinan derivatives derivatives The main alkaloidThe main alkaloid of of opium is morphine, it is the derivatives of is morphine, it is the derivatives of
morphinanmorphinan::
MMorphinanorphinan MMorphineorphine: 3,6-: 3,6-dioxydioxy--NN--methylmethyl-- 4,5-4,5-epoxymorphinen-7-7;;
In the molecule of morphine are 5 asymmetric carbon atoms. High In the molecule of morphine are 5 asymmetric carbon atoms. High reactivity of oxygroups, yields to obtain a large number of its reactivity of oxygroups, yields to obtain a large number of its
semisynthetic derivatives:semisynthetic derivatives:
Morphine hydrochloride (Morphini
hydrochloridum)
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.
HO
HO
N CH3
O * HCl * 3 H2O
Physical and chemical properties of Morphine
White needle-shaped crystals or white crystalline White needle-shaped crystals or white crystalline powder, slightly yellow during storage. Slowly soluble in powder, slightly yellow during storage. Slowly soluble in water, difficult soluble in alcohol, very slightly soluble in water, difficult soluble in alcohol, very slightly soluble in chloroform and ether.chloroform and ether.
Acid-base properties are explained by the presence of a Acid-base properties are explained by the presence of a tertiary nitrogen atom (the center core) and phenolic tertiary nitrogen atom (the center core) and phenolic hydroxyl (center of acidity). The basic properties of hydroxyl (center of acidity). The basic properties of morphine are less expresed than in ammonia, and acidic is morphine are less expresed than in ammonia, and acidic is somewhat stronger than in phenolsomewhat 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 Identification of Morphine hydrochloridehydrochloride
1. Optical rotation fromfrom -97° -97° tilltill -99° (2 % -99° (2 % water solutionwater solution). ). Appearance of the Appearance of the 5 asymmetric carbon atoms5 asymmetric carbon atoms (5, 6, 9, 13, (5, 6, 9, 13, 14) 14) gives an optical activity for a substancegives an optical activity for a substance..
2. It gives reaction of chlorides..
3.3. When to added an ammonia to a solution of a substance When to added an ammonia to a solution of a substance releasing a white crystalline precipitate which is dissolved in releasing a white crystalline precipitate which is dissolved in a solution of sodium hydroxide (according to the formation a solution of sodium hydroxide (according to the formation of sodium’s salt due to the presence of phenolic hydroxyl).of sodium’s salt due to the presence of phenolic hydroxyl).
4. It gives the reaction of alkaloids
5.5. With Phrede reagent morphine gives a violet color, passing With Phrede reagent morphine gives a violet color, passing into blue, at a staying - in green.into blue, at a staying - in green.
6.6. With Marki reagent appearance a purple coloration, rapidly With Marki reagent appearance a purple coloration, rapidly transforms into a blue-violet (unlike from codeine).transforms into a blue-violet (unlike from codeine).
7.7. Oxidation of morphine by Mandelina reagent (a solution Oxidation of morphine by Mandelina reagent (a solution of ammonium vanadate in the conc. Hof ammonium vanadate in the conc. H22SOSO44) leads to the ) leads to the
formation of the purple product.formation of the purple product.
8.8. With Erdman reagent forming a red productWith Erdman reagent forming a red product..
9.9. Pellagry reaction. At the action of a concentrated HPellagry reaction. At the action of a concentrated H22SOSO44 or a or a
concentrated HCl forming apomorphine, which from the addition concentrated HCl forming apomorphine, which from the addition of a concentrated HNOof a concentrated HNO33 becomes intense red color. If becomes intense red color. If
apomorphine is dissolved in water, which is neutralized by apomorphine is dissolved in water, which is neutralized by NaNa22COCO33 and to add 1-3 drops of iodine solution, then appearance a and to add 1-3 drops of iodine solution, then appearance a
green color. If the green solution shake with ether, the ethereal green color. If the green solution shake with ether, the ethereal layer is painted in red and water remains green.layer is painted in red and water remains green.
СС1717HH1919OO33N N → C→ C1717HH1717OO22N + HN + H22OO morphinemorphine apomorphineapomorphine
10.10. With a concentrated HNOWith a concentrated HNO33 formig an intramolecular chelate of formig an intramolecular chelate of
orange-red color.orange-red color.
11.11. The oxidizing by a potassium hexacyanoferrate (III) The oxidizing by a potassium hexacyanoferrate (III) in acidic medium with forming oxydimorphine. At the in acidic medium with forming oxydimorphine. At the further addition of iron (III) chloride to the prepared further addition of iron (III) chloride to the prepared solution it is formed "Prussian blue" (dark blue color):solution it is formed "Prussian blue" (dark blue color):
12.12. With a solution of iron (III) chloride appearance a blue coloration With a solution of iron (III) chloride appearance a blue coloration (reaction to the phenolic hydroxyl), which quickly disappears (reaction to the phenolic hydroxyl), which quickly disappears according to the oxidation of morphine by the reagent.according to the oxidation of morphine by the reagent.
13.13. Halogenation (reaction to a phenolic hydroxyl).Halogenation (reaction to a phenolic hydroxyl).
14.14. With diazonium’s salts it is formed an azo dye (due to the With diazonium’s salts it is formed an azo dye (due to the presence of phenolic hydroxyl).presence of phenolic hydroxyl).
15. The 15. The Oxidation of the secondary alcoholic hydroxyl to a ketone Oxidation of the secondary alcoholic hydroxyl to a ketone with a subsequent formation of an oximes, hydrazones, with a subsequent formation of an oximes, hydrazones, semicarbazonesemicarbazone
16. Esterification goves either a phenolic or the secondary alcoholic 16. Esterification goves either a phenolic or the secondary alcoholic hydroxyl group.hydroxyl group.
17.17. Morphine, just like other phenols, easily is oxidized. Since the Morphine, just like other phenols, easily is oxidized. Since the interaction with HJOinteraction with HJO33 it it releases areleases a free iodine. Alkaline solutions free iodine. Alkaline solutions of morphine are very easy oxidized and form oxydimorphine of morphine are very easy oxidized and form oxydimorphine (dihydromorphine, psevdomorphine, oxyimorphine):(dihydromorphine, psevdomorphine, oxyimorphine):
Quantitative determination of Quantitative determination of MorphineMorphine hydrochloride hydrochloride
Acidimetry in nonaqueous mediumin nonaqueous medium, a direct titrationa direct titration at the at the present of mercurypresent of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).Argentometric by Folgard’ method Argentometric by Folgard’ method ((Е = М.м.).Е = М.м.).Alkalimetry in Alkalimetry in ethanol-chloroform medium (Е=М.м). (Е=М.м).
StoragerStorager, , application of morphineapplication of morphine Protected from light. Opioid receptor agonist; analgesic. Strong analgesic action. Strong analgesic action. It hIt has as an an antishock action antishock action atat trauma traumass, ,
in in biggerbigger doses has a hypnotic effect. doses has a hypnotic effect. It is uIt is usseded in the in the preparation and after surgery,preparation and after surgery, at at trauma traumass, cancer, cancerss. .
Take per oral Take per oral 10-20 mg in powder10-20 mg in powder form form, or , or in hypodermic in hypodermic injectioninjection - 1% -1.0. - 1% -1.0.
MMorphinomaniaorphinomania is is a passion to morphine a passion to morphine using using. Mor. Morphphilong-ilong- is a is a 0, 5% solution of morphine hydrochloride in 30% 0, 5% solution of morphine hydrochloride in 30% aqueous solution of polaqueous solution of poliivinylpyrrolidone. Omnopon vinylpyrrolidone. Omnopon is is a a mixture of hydrochlorides of opium alkaloids (up to 50% mixture of hydrochlorides of opium alkaloids (up to 50% morphine, etc.). morphine, etc.).
Naltrexone Naltrexone hydrochloridehydrochloridel, nalorfin and Naloxone (l, nalorfin and Naloxone (SPhUSPhU) ) are are thethe antidote antidotes tos to morphine, opiate receptor antagonists. morphine, opiate receptor antagonists.
Codeine medicines• Codeine (Codeinum)
(SPhU)
4,5α-epoxy-3-methoxy-17-methyl-7,8-Didehydro-morphinan-6α-оl;
7,8-Didehydro-4,5a-epoxy-3-methoxy-17-methylmorphinan-6a-ol.
• Codeine phosphate (Codeini phosphas)
Phosphate 3-methoxy-6α-oxy-4,5α-epoxyepoxy-17-methylmorphinan-7;
7,8-Didehydro-4,5a-epoxy-3-methoxy-17-methylmorphinan-6a-ol phosphate hemihydrate.
H3CO
HO
N CH3
O * H2O
H3CO
HO
N CH3
O * H3PO4 * 1,5 H2O
Physical propertiesPhysical properties
CodeineCodeine White or almost white, crystalline powder or colourless crystals.
Solubility
Soluble in boiling water, freely soluble in ethanol (96 per cent).. It has the It has the strongest basic properties strongest basic properties among all alkaloidsamong all alkaloids (рН (рН codeine water solutioncodeine water solution 9,0). 9,0).
Codeine phosphateCodeine 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 Identification of Codeine medicinesCodeine medicines1-3. 1-3. Melting pointMelting point, , compare compare The IR spectra of the The IR spectra of the
pharmacopoeia sample and determine the maximal pharmacopoeia sample and determine the maximal absorption peaks by UV spectroscopy.absorption peaks by UV spectroscopy.
4. 4. It gives the reaction of alkaloids
5. 5. At the heated with concentrated sulfuric acid and a solution of At the heated with concentrated sulfuric acid and a solution of iron (III) chloride appearance a blue color (due to the iron (III) chloride appearance a blue color (due to the formation of apomorphine containing phenolic hydroxide).formation of apomorphine containing phenolic hydroxide).
According to the apomorphine formation codeine gives According to the apomorphine formation codeine gives positive positive Pellagry reactionPellagry reaction ( (look morphinelook morphine).).
66. . Non pharmacopoeia reaction:: а) а) With Marki reagentWith Marki reagent appearance blue-violet colorappearance blue-violet color
bb) ) with a concentrated nitric acid appearance an orange color, with a concentrated nitric acid appearance an orange color, which transfers to yellowwhich transfers to yellow..cc) ) With Phrede reagent – violet colorWith Phrede reagent – violet color;;d)d) With Erdman reagentWith Erdman reagent – – redred..
е) е) The esterification of theThe esterification of the secondary alcoholic hydroxy. secondary alcoholic hydroxy.
Identification of Identification of Codeine phosphateCodeine phosphate::а) а) BBy the reaction of the detection of phosphate ion with a solution y the reaction of the detection of phosphate ion with a solution of Silver nitrate on the formation of yellow precipitate. of Silver nitrate on the formation of yellow precipitate. POPO44
3-3- + 3Ag + 3Ag+ + AgAg 3 3 POPO4 4
bb) ) on phosphate ion with molybdenvanadium reagent on phosphate ion with molybdenvanadium reagent appearance yellow colorappearance yellow color;;POPO44
3-3- + HVO + HVO33 + 11H + 11H22MoOMoO44 + 4NH + 4NH44+ +
(NH(NH44))44[PO[PO44(MoO(MoO33))1111VOVO33] + 11H] + 11H22O + HO + H++
c c) ) Melting point of codeine base, precipitated by sodium Melting point of codeine base, precipitated by sodium hydroxide hydroxide (154-157 °С).(154-157 °С).
Quantitative determinationQuantitative determination Codeine medicinesCodeine medicines
CodeineCodeine
Acidimetry in nonaqueous in nonaqueous mediummedium, a direct titrationa direct titration at at the present of mercurythe present of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
Codeine as a strong base is Codeine as a strong base is determined by alkalimetry in determined by alkalimetry in water-alcohol medium, the water-alcohol medium, the indicator – methyl redindicator – methyl red ((Е = Е = М.м.).М.м.).
Codeine phosphateCodeine phosphate
Acidimetry in nonaqueous in nonaqueous mediummedium((Е = М.м.).Е = М.м.).
Alkalimetry in chloroform-Alkalimetry in chloroform-alcohol mediumalcohol medium, idicator - phenolphthalein ((Е = Е = М.м./2).М.м./2).
StoragerStorager, , applcation of Codeineapplcation of Codeine Protected from light.
Opioid receptor agonist; analgesic.Antitussive, mild analgesic effect. It is included in the Antitussive, mild analgesic effect. It is included in the
tablets of Kodterpine (terpinehydrate, sodium tablets of Kodterpine (terpinehydrate, sodium bicarbonate), Tablets from cough, Pentalgin, sedalgin, bicarbonate), Tablets from cough, Pentalgin, sedalgin, Solpadein, Behterrov tincture (sodium bromide, Solpadein, Behterrov tincture (sodium bromide, tincture adonis). tincture adonis).
Release form – powder, tablets. H.d.-0, 05 g; Release form – powder, tablets. H.d.-0, 05 g; H.d.d.-0, 2 g.H.d.d.-0, 2 g. Codeine phosphate as a less toxic (80% codeine base) Codeine phosphate as a less toxic (80% codeine base)
can be taken in higher doses for children. Produsing - can be taken in higher doses for children. Produsing - powder. H.d - 0, 1 g; H.d.d.-0, 3 g.powder. H.d - 0, 1 g; H.d.d.-0, 3 g.
Ethylmorphine hydrochloride(Aethylmorphini hydrochloridum)
Dionine (Dioninum)
(5R, 6S) 4,5α-epoxy-3-ethoxy-N-methylmorphine-7-еn-6-ol hydrochloride
Properties Crystalline powder of
white or nearly white. Soluble in water and 96% alcohol, practically insoluble in ether.
C2H5O
HO
N CH3
O * HCl * 2 H2O
Identification of Identification of Ethylmorphine Ethylmorphine hydrochloridehydrochloride
IR spectra.IR spectra.
Melting point of ethyl morphine base, precipitated Melting point of ethyl morphine base, precipitated by sodium hydroxideby sodium hydroxide..
At the heating a substance with a concentrated At the heating a substance with a concentrated HH22SOSO44 and a solution of FeCl and a solution of FeCl33 appearance a blue appearance a blue
color (formation of apomorphine), goes into the color (formation of apomorphine), goes into the red after the addition of a concentrated nitric acid red after the addition of a concentrated nitric acid (Pellagry reaction).(Pellagry reaction).
It gives the reaction of chlorides..
Non pharmacopoeia reaction::
а) 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 determinationQuantitative determination1) Acidimetry in nonaqueous mediumin nonaqueous medium, a direct titrationa direct titration
at the present of mercuryat the present of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
Alkalimetry in water-alcohol medium with addition of Alkalimetry in water-alcohol medium with addition of
chloroformchloroform ((Е = М.м.).Е = М.м.).StoragerStorager
Protection from lightProtection from light
ApplicationApplication Analgesic (narcotic), and antitussive medicine. For Analgesic (narcotic), and antitussive medicine. For
the treatment of the eye as anti-inflammatory agent the treatment of the eye as anti-inflammatory agent (1-2% drops or ointment). Powder, tab. at 0.01 and (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.0.015 g, the H.d. - 0,03 g; H.d.d. - 0,1 g.
Synthetic analogue of morphine on the Synthetic analogue of morphine on the pharmacological action. One of the first in this series pharmacological action. One of the first in this series have been synthesized promedol, and more recently have been synthesized promedol, and more recently - tramadol.- tramadol.
Other narcotic analgesicsOther narcotic analgesicsPentasocyn (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
(Apomorphini hydrochloridum)
5,6 dioxyapomorphine
N CH3
Àï î ðô ³í
1
2
3
4
5
6
7
8
9 10
* HCl * 3/4 H2O
N CH3
HO
HO
Glaucine hydrochloride (Glaucini hydrochloridum) Glauvent
Alkaloid from the herba of Glaucii Flavi
4,5,7,8- tetramethoxyapomorphine
hydrochloride
N CH3
H3CO
OCH3
H3CO
H3CO
* HCl
Identification of apomorphine hydrochloride1. It gives the reaction of chlorides..
2.2. WithWith HNOHNO3 3 concconc.– .– blood-red colorblood-red color..
3.3. Alkali solution extract from the substance solution a free Alkali solution extract from the substance solution a free apomorphine as a white precipitate which is dissolved in apomorphine as a white precipitate which is dissolved in excess of alkali (due to the formation of sodium salt due excess of alkali (due to the formation of sodium salt due to the presence of phenolic hydroxyl).to the presence of phenolic hydroxyl).
4.4. Oxidation reaction (Pellagry ): with iodine solution in the Oxidation reaction (Pellagry ): with iodine solution in the presence of NaHCOpresence of NaHCO33 and ether - the ether layer is painted and ether - the ether layer is painted
in red-violet color, and water becomes green.in red-violet color, and water becomes green.
5.5. Optical rotation fromOptical rotation from -46° -46° tilltill -52° ( -52° (inin HCl solutionHCl solution).).
6.6. With Marki reagentWith Marki reagent – – violet color which transfers in violet color which transfers in greengreen..
7. Vitali's-Morena reaction.
Quantitative determinationQuantitative determination1) Acidimetry in nonaqueous mediumin nonaqueous medium, a direct titrationa direct titration at the at the
present of mercurypresent of mercury (II) acetate, the indicator -the indicator - crystal violet (Е=М.м).
StoragerStorager Protected from light
ApplcationApplcation
Apomorphine hydrochlorideApomorphine hydrochloride – emetic, expectorant. At – emetic, expectorant. At poisoning it is used of 0,2-0,5 ml solution of 1% poisoning it is used of 0,2-0,5 ml solution of 1% hypodermic injection. Expectorant action - 5.1 mg orally.hypodermic injection. Expectorant action - 5.1 mg orally.
Glaucine hydrochlorideGlaucine hydrochloride– – aantitussive medicine, unlike as ntitussive medicine, unlike as codeine does not suppress breathing, non-addictive, shows codeine does not suppress breathing, non-addictive, shows a moderate hypotensive effect. Table. By 0,05 g.a moderate hypotensive effect. Table. By 0,05 g.
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