Patent GB-846482-A (GB)
Title: Reserpine derivatives and a process for the manufacture of reserpine and derivatives thereof
Filed: 1957-04-09
Abstract: The invention comprises racemic compounds of the general formula:- <FORM:0846482/IV(b)/1> and salts thereof, (wherein Y represents an unsubstituted or substituted remainder of a benzene nucleus, R is hydrogen or lower alkyl group (containing up to 5 carbon atoms), R1 is lower alkyl, R11 is hydrogen or an acyl group); also a process for their preparation and that of the corresponding optical forms by isomerising the 3-epi isomers in an acid medium. Specified substituents in ring A are halo atoms, amino, alkoxy and methylenedioxy groups especially in the 10-and/or 11-position of the yohimbane nucleus; specified acyl groups are those derived from acetic, propionic, 4-methoxybenzoic, 3,4-dimethoxy-benzoic, 3,4,5-trimethoxy-benzoic, 3,4-diethoxybenzoic 3,4-methylenedioxybenzoic, syringic, O-carbalkoxysyringic, alkoxycinnamic, furan-2-carboxylic, nicotinic, isonicotinic, thiophene-2-carboxylic, benzene sulphonic and p-toluene sulphonic acids.  Acids suitable for effecting the isomerisation are lower aliphatic acids, aromatic sulphonic acids and mineral acids, e.g. hydrohalic acids alone or in combination, and the reaction may be effected in the absence or presence of a solvent, separating the product (base or salt) by e.g. selective absorption or fractional crystallisation.  Specified salts include acid addition salts with hydrochloric, nitric, sulphuric, phosphoric, perchloric, acetic, citric, oxalic, tartaric, ascorbic, methane sulphonic, hydroxyethane sulphonic, p-toluene sulphonic, salicylic, p-amino salicylic, and acetylsalicylic acids, also salts of free carboxylic compounds with alkali and alkaline earth metals.  In examples:-(1) laevo-3-iso-reserpine is refluxed in glacial acetic acid under nitrogen, the mixture basified with ammonia, extracted with chloroform, the mixture of reserpine and 3-iso-reserpine so obtained crystallised from ethanol and resolved by treatment with cold ethyl acetate, in which 3-iso-reserpine is readily soluble; similarly (2) and (3), reserpine is obtained, using p-toluene sulphonic acid in collidine, and 3N-ethanolic HCl as acid isomerisation agents; (4), (6) and (8), as in (1), using O-acetyl methyl 3-iso-reserpate, dl-3-iso-reserpine and dl-methyl 3-iso-reserpate yielding the 3-epimers; (5) and (9), laevo and dl-3-iso-deserpidine are isomerised in acetic acid containing p-toluene sulphonic acid and the epimers separated by chromatography on a formamide-impregnated cellulose column; (7) dl-3-iso-reserpic acid is isomerised with 3N-ethanolic HBr and the resulting mixture fractionally crystallised from acetone-methylene chloride.  Likewise are obtained dl-methyl-O-acetyl-reserpate, dl-deserpidic acid and dl-methyl deserpidate.  The starting p  materials are prepared from quinone and 1,4-butadiene-1-carboxylic acid via the following intermediates:-6,9-dioxo-1,4,5a ,6,9, 10a -hexahydronaphthalene-1b -carboxylic acid, 6b -hydroxy-9-oxo-1,4,5a ,6,9, 10a -hexahydronaphthalene-1b -carboxylic acid, 2,3a -oxido-6b -hydroxy-9-oxo-1,2,3,4,5a ,6,9, 10a -octahydronaphthalene-1b -carboxylic acid, the (1b -->9b )-lactone of 3,6b -oxido-9b -hydroxy-3,4,5a ,6,9, 10a -hexahydronaphthalene-1b -carboxylic acid, the (1b -->9b )-lactone of 2a -lower alkoxy-3,6b -oxido-9b -hydroxy-1,2,3,4,5a ,6,9, 10a -octahydronaphthalene-1b -carboxylic acid, the (1b -->9b )-lactone of 2a -alkoxy-3,6b -oxido-7a -bromo-8b ,9b -dihydroxy-1,2,3,4,5a ,6 7,8,9,10a -decahydronaphthalene-1b -carboxylic acid the corresponding 8-oxocompound, 2a -alkoxy-3b -hydroxy-8-oxo-1,2,3,4,5a ,8,9, 10a -octahydronaphthalene-1b -carboxylic acid, its methyl ester, its acetate-methyl ester, 2a -alkoxy-3b -acetoxy-5b -formyl-6b -carboxymethylylohexane-1b -carboxylic acid methyl ester and compounds of the formulae: <FORM:0846482/IV(b)/2> <FORM:0846482/IV(b)/3> <FORM:0846482/IV(b)/4> <FORM:0846482/IV(b)/5>