1 / 76

Alkaloids and Derivatives of Tropane, Ecgonine, and Isoquinoline

This lecture discusses the social significance of researching alkaloids and their derivatives, such as tropane, ecgonine, and isoquinoline. It explores their chemical structure, synthesis, and pharmacological properties. Various alkaloids, including atropine and scopolamine, are highlighted as examples. The lecture also covers identification and purity tests for atropine sulfate and scopolamine hydrobromide. These alkaloids have various medical uses, including as anticholinergic medicines and antidotes to acetylcholine poisoning.

Download Presentation

Alkaloids and Derivatives of Tropane, Ecgonine, and Isoquinoline

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Lecture №24 Alkaloids derivatives of tropane, ecgonine and isoquinoline. Social significance of the research which help to find the morphine-type analgesics As. Kozachok S.S.

  2. Тropane – bicyclic condensed system, which contains the piperidine and pirrolidine cycles. Pyrrolidine Piperidine Tropane

  3. Тropaneis 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):

  4. Tropane’s alkaloids are in the plants of Solanaceae family (belladonna, datura, hioscyamus niger).

  5. The maine 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 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.

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

  7. Atropine sulphate(Atropini sulfas) (SPhU) bis(1R,ЗR,5S)-3-[(RS)-(3-hydroxy-2-phenylpropanoate) oxy]-8-methyl-8-azabicyclo[3.2.1] octanesulfate monohydrate Bis[(1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2RS)-3-hydroxy-2-phenylpropano] sulphate monohydrate. Tropine esterd,l-tropic acid sulfate monohydrate

  8. Scopolamine hydrobromide (Scopolamini hydrobromidum) Scopolamineester (-)-tropicacidhydrobromide, 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

  9. 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 solublein ethanol, very slightly solublein chloroform. Physical properties

  10. Atropine sulphate According to the physical-chemical constants: infrared spectroscopyandoptical rotation (-0,5о-+0,05о). Melting point of atropine picrate. Vitali's-Morena reaction ( on tropic acid). It gives the reactions of sulphates. 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 It gives the reactions of bromides (three reaction according to SPhU). Vitali's-Morena reaction ( on tropic acid). Melting point (192-196 °С) andoptical rotation : -22° till -26° (5 %-water solution). It gives the reaction of alkaloids Identification

  11. Formation ofbenzaldehyde

  12. 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 ofpotassium hydroxide R in methanol R. A violet colour develops.

  13. Atropine sulphate Apoatropine(<0,5%)-визначають spectrophotometrically Outsiders (foring) alkaloids Thin layer chromatography (TLC) Scopolamine hydrobromide Apoatropine, aposcopolamineand other reducing substances according to the reaction with 0,1 М of potassium permanganate – the pink colour doesn’t develop during 5 minutes. Outsiders (foring) alkaloidsare determined by the addition of ammonia solution, after that must be any turbidity observation. Purity test

  14. Atropine sulphate Acid-base titration in nonaqueous medium, a direct titrationwith potentiometricfixing of the equivalent point. (Е=М.м). Alkalimetry in ethanol-chloroform medium (Е=М.м/2). Photocolorimetry by the reaction with picric acid. Scopolamine hydrobromide Acidimetryin nonaqueous medium, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м). Argentometry by the Faience method in the acetate medium, the indicator - bromophenol blue(Е=М.м). Quantitative determination

  15. 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, ampoule0,1% - 1,0. Poisoningsubstance. 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, ampoule0,05% - 1,0. Poisoningsubstance. H.d.-0,0005 g, h.d.d.- 0,0015 g. Scopolamine butylbromide (Spazmobryu, Buscopan, Buskotsin-M) Storager, applcation

  16. Homatropinehydrobromide (Homatropini hydrobromidum) Tropine ester of almond acid hydrobromide (N-methyl-8-azoniabicyclo[3.2.1]oct-3-yl) 2-hydroxy-2-phenylacetate bromide Tropacyn, Diphenyltropanehydrochloride (Tropacinum) Tropine ester of diphenylacetate acids hydrochloride Synthetic analogues of atropineAtropine 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

  17. Tropaphenine (Tropaphenum). Expressed α-adrenaline receptors agonist, weak anticholinergic. Producing:lyophilized powder for injection. Troventoline(Troventolum). Bronchodilatory drug. Aerosol. Atrovent ((Ipratropiumbromide). Bronchodilatory drug. Aerosol.

  18. Obtaiing of syntheticanalogs of atropine According to the interaction between tropine and according acid or its chlorhydride:

  19. Homatropinehydrobromide 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, alcoholand chloroform, practically insoluble in ether and benzole. Physical properties

  20. Homatropinehydrobromide 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 КОН solution –white sediment, it’s 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. Doesn’t give Vitali's-Morena reaction. Tropacyn Give Vitali's-Morena reaction(ondiphenylacetate acid). Melting point. It gives the reaction of alkaloids It gives the reactions of chlorides (two reaction according to SPhU). Hydroxamic reaction. Identification

  21. Vitali's-Morena reactionon tropacyn:

  22. Homatropinehydrobromide Acidimetryin nonaqueous medium, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м). Alkalimetry inwater-alcoholmedium at the present in chloroform (Е=М.м). Tropacyn Acidimetryin nonaqueous medium, a direct titrationat the present of mercury(II) acetate, the indicator - crystal violet(Е=М.м). Tropacyn in tabletsis determined argentometric by Folgard’ method(Е=М.м). Quantitative determination

  23. Homatropinehydrobromide 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. Poisoningsubstance. 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. Poisoningsubstance. H.d.-0,03 H.d.d.- 0,1 g. Storage, application

  24. Tropane’s alkaloids ecgonine types Cocainehydrochloride (Cocaini hydrochloridum) Hydrochloride of methyl esterbenzoylecgonine • Cocaine is methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[ 3.2.1]octane-2-carboxylate hydrochloride

  25. (Erythroxylon Coca) May be obtained from the leaves of Erythroxylum coca Lam. and other species of Erythroxylum or by synthesis.

  26. 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 • It gives the reactions of chlorides. • Melting point (not lell 195 °С); optical rotation - from -71 ° till -73° (2,5 %-water solution); specific absorption rate. • Hydroxamic reaction (on the estergroup). • It gives the reaction of alkaloids

  27. 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.

  28. 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

  29. Purity test • Unacceptable impuritycinnamoylcocaineand other reducing substances – with КМnО4 solutionit 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 • Acidimetryin nonaqueous medium, a direct titrationat 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.

  30. 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.

  31. 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).

  32. 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.

  33. 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 contains ballast substances, a little papaverine,and 2/3 half of all narcotine. Alkaloids are extracted by the dichloroethane Sediment contains morphine, narcotine, meconate ammonium which are not soluble in alcohol Dichloroethane extract Contains 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 Papaverine is purified according to the formation of a hard soluble salt Water extract (concentrated in vacuum at 60-70 0C add ammine and ethanol Filtrate acidified by an acetic acid at the present of sodium acetate and extracted by dichloroethane Water solution contains codeine, thebaine and other alkaloids which are formed with acetic acid water solubility acetates at the present of sodium acetate

  34. 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 is extracted by an acetic acid. Narcotine as a very weak base doesn’t form the salt. And it is in sediment. The filtrate contains meconate ammonium Filtrate contains morphine acetate to add ammine and to filtrate Morphine is purified by a crystalisation from a diluted hydrochloric asid solution Narcotine sediment is purified by a crystalisation from an alcohol or acetone meconate acid

  35. Papaverinehydrochloride (Papaverini hydrochloridum) 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy isoquinolinehydrochloride Drotaverinehydrochloride (Drotaverini hydrochloridum) NО-Shpa (Nospanum) 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro- isoquinoline hydrochloride Alkaloids of 1-benzylisoquinoline derivatives

  36. Physical properties Papaverinehydrochloride (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(formingdimethoxyisoquinolineanddimethoxytoluol) andoxidized by КMnO4 (oxidation products arepyridine- threecarbonic acid and 3,4-dimethoxybenzoate (veratic) acid). It has reducing property according to the two aromatic fragmentsbounding by methylene group, as well as a four methoxide groups. Drotaverinehydrochloride Yellow crystalline powder. Soluble in water and ethanol, not soluble in an ether.

  37. Identification of Papaverinehydrochloride • Determination of specific absorption by UV spectroscopy. • Melting point of a papaverine base after it is settled down by ammonia.To 10 ml of solution S (see Tests) add5 ml of ammonia R dropwise and allow to standfor 10 min. The precipitate, washed and dried, melts (at 146 °C to 149 °C. • 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. • It gives reaction of chlorides. • 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;

  38. 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

  39. 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.

  40. Drotaverinehydrochloride 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.

  41. Quantitative determinationof papaverine hydrochloride • Alkalimetry in a mixture mediumof an alcohol and 0,01М chloric acid with potentiometricfixing of the equivalent point. (Е=М.м). • Acidimetryin nonaqueous medium, a direct titrationat 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.

  42. Papaverine hydrochloride Protected from light Phosphodiesterase inhibitor; smooth muscle relaxant. Using per oral 40-80 mg 3-4 times a day, parenteral1-2 ml of 2% solution. Producing - powder, tablets 40 mg, ampoules 2% - 2,0, suppositories0,2 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, injecti/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) Storage, application

  43. Alkaloidof morphinan derivatives The main alkaloidof opiumis morphine, it is the derivatives of morphinan: Morphinan Morphine: 3,6-dioxy-N-methyl- 4,5-epoxymorphinen-7;

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

  45. Morphine hydrochloride (Morphini hydrochloridum) Three hydratehydrochloride 3,6-dioxy-4,5-epoxy-17 methylmorphinen-7 7,8-Didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol hydrochloride trihydrate.

  46. 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.

More Related