Patent GB-585250-A (GB)
Title: Improvements in and relating to the production of esters of penicillamine
Filed: 1944-12-01
Abstract: A penicillamine ester is obtained by treating an ester of a thiazolidine of the general formula <FORM:0585250/IV/1> wherein R represents an alkyl group containing not more than four carbon atoms and R1 represents hydrogen or a lower alkyl group as defined above, with a hydrolysing agent under such conditions as to effect preferential hydrolysis of the residue <FORM:0585250/IV/2> The thiazolidine preferred is isopropylidene penicillamine, and hydrolysis is advantageously achieved by treating with mercuric chloride followed by treatment with hydrogen sulphide.  In examples: (1) isopropylidenepenicillamine methyl ester, in methanol, is treated with methanolic mercuric chloride at room temperature, the residue is treated with water and mercuric sulphide is precipitated by sulphuretted hydrogen, penicillamine methyl ester hydrochloride being isolated by evaporating the aqueous filtrate; (2) isopropylidenepenicillamine butyl ester hydrochloride is treated with mercuric chloride in butanol, being thereafter processed as in (1) to isolate penicillamine-n-butyl ester hydrochloride; (3) aqueous isopropylidene penicillamine methyl ester hydrochloride is treated with nitrogen prior to boiling the solution in presence of nitrogen, and the solution is evaporated in vacuo to isolate penicillamine methyl ester hydrochloride; (4) isopropylidene penicillamine ethyl ester, in alcohol, is treated with ethanolic mercuric chloride and processed as in (1) to isolate penicillamine ethyl ester hydrochloride.  The corresponding "commercial amyl" and benzyl ester hydrochlorides may be obtained similarly; (5) isopropylidene penicillamine isopropyl ester hydrochloride, in isopropyl alcohol, is treated with mercuric chloride in isopropyl alcohol, being thereafter processed as in (1) to isolate penicillamine isopropyl ester hydrochloride.  Isopropylidene penicillamine is prepared by condensing penicillamine with acetone.  Isopropylidene penicillamine methyl ester is prepared by treating an ice-cold suspension of isopropylidene penicillamine in methyl alcohol with ethereal diazomethane and precipitating the resulting ester by adding water. Isopropylidene penicillamine-n-butyl ester is prepared by treating isopropylidene penicillamine, suspended in boiling benzene, with dry hydrogen chloride, and, 2 hours after solution is complete, evaporating the whole to small bulk which is refluxed with acetone to isolate the corresponding hydrochloride, from which the parent base may be obtained by treatment with aqueous sodium carbonate. Isopropylidene penicillamine ethyl ester is prepared by saturating an ice-cold suspension of isopropylidene penicillamine hydrochloride in ethanol with dry hydrogen chloride and heating under reflux until a clear solution is formed, boiling being continued for 30 minutes, prior to evaporation in vacuo and processing the residue to isolate the product.  The propyl-, n-amyl- and n-hexyl isopropylidene penicillamine esters are prepared similarly.  Isopropylidene penicillamine isopropyl ester is prepared by saturating an ice-cold suspension of isopropylidene penicillamine hydrochloride in isopropyl alcohol with dry hydrogen chloride, heating under reflux for about 6 hours, evaporating the filtrate, treated with benzene, in vacuo, triturating the residue with acetone, making alkaline with aqueous sodium bicarbonate and treating the precipitated oil in light petroleum with dry hydrogen chloride to isolate the crystalline product.  Specification 584,918 is referred to.