GB1272866A - Production of penicillamine - Google Patents

Abstract

1,272,866. Synthesis of penicillamine. DEUTSCHE GOLD UND SILBER SCHEIDEANSTALT. 28 Aug., 1969 [6 Sept., 1968], No. 42798/69. Heading C2C. Penicillamine or its hydrochloride salt is prepared by (1) reacting isobutyraldehyde with sulphur or a sulphur containing compound which releases sulphur under the reaction conditions, e.g. polysulphides, and with ammonia or NH 4 NO 3 .2NH 3 , optionally in the presence of a secondary or tertiary amine, the water formed being removed azeotropically, (2) treating the resulting 2 - isopropyl - 5,5 - dimethyl #<SP>3</SP>- thiazoline with anhydrous HCN to give 2-isopropyl - 5,5 - dimethylthiazolidino - 4 - carbonitrile, (3) heating the latter (optionally without purification or in the form of its hydrochloride) with an excess of concentrated HCl at 70-110‹ C. in the absence of oxygen and (4) either (i) evaporating the reaction mixture to obtain a mixture (A) consisting of 2-isopropyl- 5,5 - dimethylthiazolidino - 4 - carboxylic acid hydrochloride, ammonium chloride and small quantities of D,L-penicillamine hydrochloride, boiling the mixture (A) in a liquid watermiscible carbonyl compound (B), cooling and suction-filtering the liquid after which the resulting solid substance (C) is extracted hot with a liquid water-miscible carbonyl compound (B) and the extract is subjected to steam distillation; or (ii) treating the reaction mixture as in (i) to obtain the solid substance (C) which is subjected to steam distillation, the residue concentrated by evaporation to dryness and ammonium chloride formed separated off by extraction with an alcohol; or (iii) treating the reaction mixture as in (i) to obtain the solid substance (C) which is subjected to steam distillation, the residue concentrated by evaporation to dryness and the dry residue, optionally after having been boiled in a carbonyl compound (B), is extracted hot with this compound and the extract boiled with water; or (iv) treating the reaction mixture as in (i) to obtain the mixture (A) which is directly treated with anhydrous methanol, ethanol or isopropanol and the resulting solution subjected to steam distillation; or (v) subjecting the reaction mixture to steam distillation, concentrating the residue by evaporation to dryness and separating off ammonium chloride formed by extraction with an alcohol; or (vi) subjecting the reaction mixture to steam distillation, concentrating the residue by evaporation to dryness and extracting the residue, optionally after having been boiled in a carbonyl compound (B), hot with this compound and boiling the extract with water; the hydrochloride formed being optionally converted into free D,L-penicillamine which may subsequently be resolved into its optical isomers, e.g. using brucine.