Reserpine(Structure Elucidation, Extraction and Isolation)
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Reserpine is an indole alkaloid primarily extracted from Rauwolfia species, used in treating hypertension and other disorders. The document details its structural elucidation, extraction processes, mode of action by blocking neurotransmitter transporters, and its synthesis. It also discusses reserpine's classification, therapeutic applications, dosage, side effects, and identification tests.
![Chemistry:
Reserpine is an indole Alkaloid
Structure:
IUPAC Name:
(3β,16β,17α,18β,20α)-11,17-Dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-
16-carboxylic acid methyl ester 3,4,5-trimethoxybenzoyl methyl reserpate
Melting point: 262-2700C.
16-Apr-20 Krishna Pharmacy College, Bijnor 28](https://image.slidesharecdn.com/reserpine-200417023621/85/Reserpine-Structure-Elucidation-Extraction-and-Isolation-28-320.jpg)
Reserpine(Structure Elucidation, Extraction and Isolation)
- 1. Reserpine (Structural elucidation, Extraction & Isolation) Prepared By: MOHAMMAD KHALID (Assistant Professor) Krishna Pharmacy College, Bijnor (UP)
- 2. content Introduction Constitution of reserpine Structure of Reserpic acid Structure of Yobyrine Synthesis of Yobyrine Structure of Reserpine Synthesis of Reserpine Classification Extraction Isolation: Identification test Mode of Action 16-Apr-20 Krishna Pharmacy College, Bijnor 2
- 3. introduction Reserpine is the main constituent of Rauwolfia species,perticularly Rauwolfia serpentina & Rauwolfia vomitoria. It is mainly used for the treatment of hypertension, headache, tension, asthma & dermatological disorders. 16-Apr-20 Krishna Pharmacy College, Bijnor 3
- 4. Constitution of reserpine 1. Molecular formula:- C33H40N2O9 2. Presence of five methoxy groups:- By zeisel method i.e. when treated with HI yields five molecules of methyl iodide indicating the presence of five methoxy groups. 3. Nature of ‘N’ atom:- a) Secondary ‘N’ – Formation of monoacetyl derivative with acetic anhydride indicates secondary ‘N’ . b) Tertiary ‘N’- Reserpine forms quaternary ammonium salts with CH3I that indicating one of ‘N’ is tertiary. 16-Apr-20 Krishna Pharmacy College, Bijnor 4
- 5. 4. Hydrolysis:- Hydrolysis of reserpine yields mixture of i) Methyl alcohol ii) 3,4,5-trimethoxy benzoic acid iii) Acid (A) of composition C33 H40 N2 O9 H2 O NaOH CH3 OH C22 H28 N2 O5 COOH OMe OMe MeO + 2 Hydrolysis + + 16-Apr-20 Krishna Pharmacy College, Bijnor 5
- 6. As reserpine does not contain -COOH & - OH groups, hence its hydrolysis product reveal that reserpine is a di-ester. The ester linkage in reserpine has been further confirmed by its reduction with 5. Reduction:- C33 H40 N2 O9 LiAlH4 C22 H30 N2 O4 CH2 OH OMe OMe MeO Reserpic Alcohol + 16-Apr-20 Krishna Pharmacy College, Bijnor 6
- 7. Structure of Reserpic acid a) Molecular formula:- b) Presence of one carboxyl group:- By usual tests e.g. silver salt method c) Presence one –OH group:- Reserpic acid on oxidation yields a ketone that means it has secondary alcoholic group. d) Nature of two methoxy groups:- By zeisels method. e) Nature of two ‘N’ atom:- It shown that it contains two ‘N’ atoms in heterocyclic ring in the form of- i) Secondary ‘N’ ii) Tertiary amino group C22 H28 N2 O5 16-Apr-20 Krishna Pharmacy College, Bijnor 7
- 8. f) Reduction of reserpic acid:- On reduction with yields reserpic alcohol. g) Oxidation of reserpic acid:- On oxidation with KMnO4 it gives 4-methoxy N- oxalyl anthranilic acid. Thus one of the methoxyl group is present in meta position to –NH group NHCOCOOHMeO COOH KmnO4 C22 H28 N2 O5 4-methoxy N-oxalyl Anthranilic acid oxidation Reserpic acid 16-Apr-20 Krishna Pharmacy College, Bijnor 8
- 9. h) Fusion with KOH :- When reserpic acid is fused with potash it yields 5- hydroxy isophthalic acid. One of the acidic groups of isophthalic acid must be present in m- position to each other this confirm by the fact that reserpic acid when heated with acetic anhydride yields a gamma lactone. C22 H28 N2 O5 OH COOH HOOC KOH Fusion 5-hydroxy isophthalic acid C22 H28 N2 O5 AC2 O OOC v-lactone 16-Apr-20 Krishna Pharmacy College, Bijnor 9
- 10. i) Dehydrogenation:- When methyl reserpate is dehydrogenated with selenium it yields a hydrocarbon of molecular formula - This hydrocarbon is also obtained by dehydrogenation of Yohimbine with selenium & was therefore named as Yobyrine. C19 H16 N2 Methyl reserpate Se Dehydrogenation C19 H16 N2 DehydrogenationSe Yobyrine Yohimbine16-Apr-20 Krishna Pharmacy College, Bijnor 10
- 11. Structure of Yobyrine 1. Molecular formula:- 2. Zinc Distillation:- 3. Oxidation:- When yobyrine is oxidized with permangnate it yields phthalic acid C19 H16 N2 C19 H16 N2 Zn dust N N H C2 H5 Distillation + Isoquinoline 3-ehtyl indole C19 H16 N2 KmnO4 CH3 COOH cr2 o3 COOH COOH Pthalic acid o-Toulic acid 16-Apr-20 Krishna Pharmacy College, Bijnor 11
- 12. 4. Condensation with aldehydes:- Yobyrine gives condensation products suggesting the presence of pyridine ring with a methylene substitution adjacent to the nitrogen. On the basis of above facts following structure has been postulated for yobyrine. N H N CH3 Yobyrine 16-Apr-20 Krishna Pharmacy College, Bijnor 12
- 13. Synthesis of Yobyrine N H NH2 CH3 CH2ClOC NH N H CO CH2 CH3 POCl3 CH3 N N H CH2 2-(3-indolyl)ethyl amine O-tolyl acetyl chloride + 1) -HCl 2)Reduction 2H- dehydrogenation N H N CH3 Yobyrine 16-Apr-20 Krishna Pharmacy College, Bijnor 13
- 14. j) As Yobyrine is formed from reserpic acid it means that reserpic acid may possesses the following types of skeleton structures. k) From the fact 5(g) it follows that one of the methoxyl group is present in m-position to the NH group of indole i.e. on C-11 i.e. Ome is at C-11. N N H SKELETON STRUCTURE 16-Apr-20 Krishna Pharmacy College, Bijnor 14
- 15. Reserpic acid when dehydrogenated yields 11-hydroxy-16- methyl yobyrine,this may be only formed if –COOH group is present on C-16 From the step (h) it follows that –COOH & -OH group are in m-position to each other but –COOH group is present at C- 16 therefore –OH group must be at C-18. C22 H28 N2 O5 N N H CH2 OH CH3 CH3 Se dehydrogenation 11-hydroxy-16-methyl yobyrine 16-Apr-20 Krishna Pharmacy College, Bijnor 15
- 16. From purely biogenic reasons, the 2nd methoxyl group has been assigned position C-17. On the basis above mentioned facts the structure of reserpic acid may be N N H OH MeO OMe HOOC Reserpic acid 16-Apr-20 Krishna Pharmacy College, Bijnor 16
- 17. Structure of Reserpine As reserpine is di-ester of reserpic acid, it means that, N N H OH MeO OMe HOOC CH3 OH COOH OMe OMe MeO N H N O MeO H3 COOC OMe CO OMe OMe OMe Reserpic acid + + Reserpine -2 H2O 16-Apr-20 Krishna Pharmacy College, Bijnor 17
- 18. Synthesis of Reserpine The structure of reserpine has been confirmed by its synthesis given by Woodward et.al. O O H2 C C C CH COOH O O CH2 CH COOH CH CH NaBH4 OH O COOH C6 H5 COOH OH O COOH O Ac2 O + Diels Alder reaction Adduct Reduction of less hindered ( =CO) phenoxy benzoic acid p-Benzoquinone 16-Apr-20 Krishna Pharmacy College, Bijnor 18
- 19. Synthesis continue….. O O OCO OH O CO O O CO O CH3 ONa CH3 OH O CO OMe O H2 SO4 O CO OMeOH O Br Cro3 Aluminium isopropoxide - -H2O NBS- 16-Apr-20 Krishna Pharmacy College, Bijnor 19
- 20. Synthesis continue….. O CO OMeO Br O Zn CH3 COOH O OH COOH OMe / CH2 N2 Ac2 O OSO4 -H2 O i) ii) Pyridine iii) OH OH O OAc MeO COOCH3 HIO4 CH2 N2 OAc CH2 CHO COOCH3 MeO COOCH3 i) ii) 6-methoxy tryptamine N H NH2MeO 16-Apr-20 Krishna Pharmacy College, Bijnor 20
- 21. Synthesis continue….. N N H MeO C H CH2 OAc OMe H3 COOC H3 COOC NaBH4 CH3 OH N H MeO OAc OMe H3 COOC N O POCl3 NaBH4 ii) i) i) ii) 16-Apr-20 Krishna Pharmacy College, Bijnor 21
- 22. Synthesis continue….. OAc OMe H3 COOC N N H MeO OMe N N H OC O OMe i)Resolve ii)NaOH iii)Hcl iv)DCC 16-Apr-20 Krishna Pharmacy College, Bijnor 22
- 23. Synthesis continue….. Isomerisation CH3 OH OMe OMe HOOC OMe (CH3 )3 CCOOH N OMe N H MeO OC O OMe H3 COOC N N H MeO OCO OMe OMe OMe Reserpic acid Lactone Reserpine 16-Apr-20 Krishna Pharmacy College, Bijnor 23
- 24. classification Kingdom : Plantae Division : Magnoliophyta Class : Magnoliopsida Order : Gentianales Family : Apocynaceae Genus : Rauwolfia Species : serpentina 16-Apr-20 Krishna Pharmacy College, Bijnor 24
- 25. Geographical Source: Asia, America Morphology: Snake shaped, brown coloured, longitudinal wrinkles tapering towards the end 16-Apr-20 Krishna Pharmacy College, Bijnor 25
- 26. extraction Plant material Macerated with alcohol Alcholic extract Reduce in volume and residue is treated in water Filter Ppt insoluble in water Ppt contain reserpine16-Apr-20 Krishna Pharmacy College, Bijnor 26
- 27. ISOLATION: Ppt of crude drug Add benzene with continuous stirring Filter, concentrate it Filter Filtrate Ppt remove • Dry in vaccum • Add 150 ml acetic acid in methanol and ammonium solution • pH is adjusted to 8.5 and stand • Crystalline substance appear • Dry, add benzene • Then it is chromatographed on 100 gm acid washed alumina • Further fraction eluted with sequance of solvent from chloroform • And crystallized from benzene 16-Apr-20 Krishna Pharmacy College, Bijnor 27
- 28. Chemistry: Reserpine is an indole Alkaloid Structure: IUPAC Name: (3β,16β,17α,18β,20α)-11,17-Dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban- 16-carboxylic acid methyl ester 3,4,5-trimethoxybenzoyl methyl reserpate Melting point: 262-2700C. 16-Apr-20 Krishna Pharmacy College, Bijnor 28
- 29. Identification test Chemical test: Freshly fractured surface of the root when treated with concentrated HNO3 shows red coloured medullary rays. Reserpine gives a violet colour with vanillin in acetic acid Rauwolfia serpentina. Other test for alkaloid: Dragondrof test Mayer test Hagers test Wagners test Tannic acid test 16-Apr-20 Krishna Pharmacy College, Bijnor 29
- 30. Mode of Action Reserpine acts by blocking the vasicular monoamine transporter VMAT, which normally transports free norepinephrine, serotonin, and dopamine from the cytoplasm of the presynaptic nerve into vesicles for subsequent release into the synaptic cleft. The unprotected neurotransmitters then metabolized by MAO and therefore never reach the synapse. By this mode of action this give mainly the antihypertensive action and also use in the treatment of dykynesia mania etc. 16-Apr-20 Krishna Pharmacy College, Bijnor 30
- 31. Therapeutic application: Essential hypertension Mild anxiety Dyskinesia Psychosis symptoms Maintenance dose: 100 to 250 mg (once a day) Side effects: Nasal congestion Nausia Vomiting Gastric intolerance Gastric ulceration diarrhoeia 16-Apr-20 Krishna Pharmacy College, Bijnor 31
- 32. References 1)“ Organic Organic Chemistry of Natural Products ”- by Gurudeep Chatwal ,Vol-I. 2)“ Organic Chemistry ”by I.L.Finar , Vol-II . 3)“Pharmacognosy” by C.K.Kokate , A.P.Purohit , S.B.Gokhale 4) http://www.authorstream.com/Presentation/agarawaldinesh47- 1168554-reserpine/ 5)http://www.authorstream.com/Presentation/abdulrazzaqM.PHAR M-642751-reserpine-structural-elucidation/ 16-Apr-20 Krishna Pharmacy College, Bijnor 32
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