Patent GB-744290-A (GB)
Title: Manufacture of alkaloid derivatives
Filed: 1954-05-07
Abstract: The invention comprises (1) reserpic acid and its derivatives in which at least the carboxylic group is esterified, and salts and quaternary ammonium compounds thereof, but excluding reserpine and its salts, and (2) the alkaline hydrolysis of reserpine to reserpic acid or an ester thereof, the esterification of the carboxylic and/or the hydroxyl group in reserpic acid and the formation of salts and quaternary compounds of reserpic acid and its esters.  The hydrolysis of reserpine can be effected with an alcoholic alkali hydroxide, the esterified hydroxyl being split first and then the esterified carboxyl.  If a metal alcoholate in anhydrous alcohol is used ester-interchange occurs.  The carboxylic group of reserpic acid can be esterified with a diazoalkane or with an alcohol and a strong acid.  For esterifying the hydroxyl group there is used an acid halide or anhydride. Examples show the following reactions:-(1) reserpine (obtained from Rauwolfia serpentina as in Specification 734,108) hydrolysed to reserpic acid (via hydrochloride) and converted to potassium salt; (2) methyl reserpate from reserpic acid (or its hydrochlorides) and diazomethane; (3) ethyl reserpate from reserpic acid (or its hydrochloride) and diazoethane; (4) reserpine hydrolysed to reserpic acid, methyl reserpate and 3:4:5-trimethoxybenzoic acid; (5) reserpine hydrolysed with anhydrous alkanol to give methyl, ethyl and n-butyl reserpate; (6) methyl reserpate reconverted to reserpine with 3:4:5-trimethoxybenzoyl chloride; (7) methyl reserpate esterified with the halides of veratric, anisic, pyromucic, nicotinic, cinnamic, phenylacetic, 3:4-dichlorobenzoic, isocaproic, 3:4:5 - trimethoxycinnamic, benzoic, carbethoxysyringic, methanesulphonic and toluene-p-sulphonic acids, and with acetic anhydride; (8) ethyl reserpate esterified with acetic anhydride and with 3:4:5-trimethoxybenzoyl chloride; (9) the carbethoxysyringic ester of methyl reserpate hydrolysed to the syringic ester and the latter converted to reserpine with diazomethane; (10) methyl reserpate and reserpine converted to methiodides.  In general, the hydroxyl group may be esterified with aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic acids, or with sulphonic acids.  Other specified acids are propionic, chloropropionic, butyric, succinic, methylethylacetic, methylethylglycollic, stearic, chloracetic, aminoalkanoic, tropic, mandelic, mono- and di-methoxycinnamic, toluic, triethoxybenzoic, piperonylic, salicylic, p-hydroxybenzoic, resorcylic, protocatechuic, orsellinic, gallic, vanillic, isovanillic, chlorobenzoic, nitrobenzoic, aminobenzoic, mono- and di-methoxybenzoic, phthalic, naphthoic, thienoic, picolinic, isonicotinic, quinolinecarboxylic and sulphanilic. Reserpic acid forms salts with alkali and alkaline earth metals, and the acid and its esters form salts with acids such as hydrohalic, sulphuric, phosphoric, nitric, isethionic, acetic, tartaric, citric and toluenesulphonic.  Quaternary salts can be formed with alkyl halides, sulphates and sulphonates. 3:4:5-Trimethoxycinnamoyl chloride and bromide are prepared by treating the corresponding acid with thionyl chloride and bromide respectively.