Alkaloids derivatives of tropane, ecgonine and isoquinoline. Social significance of the research which help to find the morphine-type analgesics.
Тropane – bicyclic condensed system, which contains the piperidine and pirrolidine cycles.
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):
Tropane’s alkaloids are in the plants of Solanaceae family (belladonna, datura, hioscyamus
The main representatives of topane’s alkaloids are racemic atropine, its left rotation isomer – hyoscyamine and the analogue of hyoscyamine – scopolamine.
Atropine was first isolated from belladonna in
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)
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-phenylpropanoate] sulphate monohydrate.
Tropine ester d,l–tropic acid sulfate monohydrate
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
Physical properties
Atropine sulphate
White or almost white, crystalline powder or colourless crystals. Very soluble in water, freely soluble in ethanol (96 per cent).
Melting at 190°С and decomposing.
Scopolamine hydrobromide
White or almost white, crystalline powder or colourless crystals. Freely soluble in water soluble in ethanol, very slightly soluble in chloroform.
Identification
Atropine sulphate
1. According to the physical-chemical constants: infrared spectroscopy and optical rotation (-0,5о-+0,05о).
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:
а) Melting point of atropine base (115-117 °С) 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:
Scopolamine hydrobromide
1. It gives the reactions of bromides (three reaction according to SPhU).
2. Vitali’s-Morena reaction ( on tropic acid).
3. Melting point (192-196 °С) and optical rotation : -22° till -26° (5 %-water solution).
4. 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. Apoatropine(<0,5%)-визначають spectrophotometrically
Outsiders (foring) alkaloids
Thin layer chromatography (TLC)
Scopolamine hydrobromide
1. Apoatropine, aposcopolamine and other reducing substances according to the reaction with
2. Outsiders (foring) alkaloids are determined by the addition of ammonia solution, after that must be any turbidity observation.
Quantitative determination
Atropine sulphate
1) Acid-base titration ionaqueous medium, a direct titration with potentiometric fixing of the equivalent point. (Е=М.м).
2) Alkalimetry in ethanol–chloroform medium (Е=М.м/2).
3) Photocolorimetry by the reaction with picric acid.
Scopolamine hydrobromide
1) Acidimetry ionaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator – crystal violet (Е=М.м).
2) Argentometry by the Faience method in the acetate medium, the indicator – bromophenol blue (Е=М.м).
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..-
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.-
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 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,N-dimethyl-8-azoniabicyclo[3.2.1]oct-3-yl) 2-hydroxy-2-phenylacetate bromide
Tropacyn, Diphenyltropane hydrochloride (Tropacinum)
Tropine ester of diphenylacetate acids hydrochloride
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 synthetic analogs of atropine
According to the interaction between tropine and according acid or its chlorhydride:
Physical properties
Homatropine hydrobromide
White or almost white, crystalline powder. Freely soluble in water, slightly soluble in alcohol, very slightly soluble in chloroform, practically insoluble in ether.
Tropacyn
White or almost creamy white crystalline powder. Freely soluble in water, alcohol and chloroform, practically insoluble in ether and benzole.
Identification
Homatropine hydrobromide
1. It gives the reactions of bromides (three reaction according to SPhU).
2. It gives the reaction of alkaloids
3. With iodine solution settled down the brown sediment of substance periodide.
4. With КОН solution –white sediment, it’s dissolved in the excess of the reagent.
5. 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).
6. Hydroxamic reaction .
7. Doesn’t give Vitali’s-Morena reaction.
Tropacyn
1. Give Vitali’s-Morena reaction (on diphenylacetate acid).
2. Melting point.
3. It gives the reaction of alkaloids
4. It gives the reactions of chlorides (two reaction according to SPhU).
5. Hydroxamic reaction.
Vitali’s-Morena reaction on tropacyn:
Quantitative determination
Homatropine hydrobromide
1) Acidimetry ionaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator – crystal violet (Е=М.м).
2) Alkalimetry in water–alcohol medium at the present in chloroform (Е=М.м).
Tropacyn
1) Acidimetry ionaqueous medium, a direct titration at the present of mercury (II) acetate, the indicator – crystal violet (Е=М.м).
2) Tropacyn in tablets is determined argentometric by Folgard’ method (Е=М.м).
Storage, application
Homatropine hydrobromide
Protected from light.
Anticholinergic (midriatic) medicine. Using eye drops 0,25-0,5-1% solutions. Doesn’t use at the treatment of glaucoma.
Producing – powder, ampoules 0,1% – 1,0. Poisoning substance. H.d.-0,001g, H.d.d.-
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.-
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
(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 °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 ionaqueous 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).
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.-
Alkaloid – isoqinoline 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 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 (b -oxy- g -pyrone- a -dicarboxylic), lactic and sulfuric acids. Narcotine and papaverine as a very weak basis are in a
Alkaloids of 1-benzylisoquinoline derivatives
Papaverine 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
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 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
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
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 violet sediment, which is dissolved in an alcohol and gives violet-red colour.
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References:
1. British Pharmacopoeia, 2009. – 10952 p.
2. European Pharmacopoeia, 2008. – 7895 p.
3. David G. Watson. Pharmaceutical analysis. – New York: Churchill Livingstone, 2000. – 400 p.
