Patent GB-600245-A (GB)
Title: Improvements in and relating to the synthesis of heterocyclic organic compounds containing sulphur
IPC: C07D513/04
Filed: 1944-05-12
Abstract: Thiazolidines of the general formula:-<FORM:0600245/IV(b)/1> are treated with phosphorus oxychloride or less preferably another dehydrating agent such as acetic anhydride to produce compounds of the general formula <FORM:0600245/IV(b)/2> R2 being an alkyl-, aralkyl- or arylacyl radical, R3 being hydrogen or an alkyl, aralkyl or aryl ester radical, R4 and R5 being hydrogen or an alkyl, aralkyl or aryl radical, and R5 and R7 being an alkyl, aralkyl or aryl radical, and the latter compounds are then treated with mercuric chloride, zinc chloride or cadmium chloride to yield by ring-opening 2-substituted a -(1-imidazolyl)-b -thiol carboxylic acids or esters thereof.  Advantageously R2 may be a para-hydroxy or para-alkoxy phenyl acetyl group, e.g. a p-acetoxyphenyl acetyl group, R7 therefore becoming a p-hydroxy or p-acyloxy phenyl acetyl group. Such products have a structure analogous to that of a portion of the penicillin-III molecule.  In examples: (1) caproylamino thiazolidine hydrochloride, suspended in phosphorus oxychloride, is treated with syrupy phosphoric acid, and the residue after concentrating in vacuo, is diluted with dioxan and added to aqueous sodium bicarbonate, the diketopiperazine derivative:- <FORM:0600245/IV(b)/3> being isolated as by a by-product.  The filtrate is extracted with butanol and concentrated in vacuo and the residue, in chloroform, is precipitated with ether to isolate "decarboxy-dihydropenillic-I acid":- <FORM:0600245/IV(b)/4> which is treated in aqueous methanol with aqueous 5 per cent mercuric chloride, and the resulting ppt. is decomposed with hydrogen sulphide to isolate crude r-dihydropenillamine-I hydrochloride:- <FORM:0600245/IV(b)/5> (2) p-Hydroxyphenylacetic acid is acetylated to p-acetoxyphenylacetic acid, which is converted into the corresponding acid chloride, and added to aminoacetal containing saturated aqueous sodium bicarbonate and p-acetoxy phenylacetylamino diethylacetal is isolated, heated with dl-penicillamine (b b -dimethylcysteine) hydrochloride to isolate the corresponding thiazolidine hydrochloride, treated with phosphorus oxychloride, to form crude dl-penillamine-III hydrochloride; (3) l-penicillamine hydrochloride is warmed with caproylaminoacetal to 60 DEG  C. to yield the corresponding thiazolidine hydrochloride, and the a -thiazolidine hydrochloride is prepared similarly.  The optically pure thiazolidine hydrochlorides are converted by phosphorus oxychloride into d-(-)-, and l-(+)-dihydro-penillamine-I hydrochlorides are each obtained crystalline; (4) l-penicillamine hydrochloride and phenylacetylamino-diethylacetal are melted together to yield l-penilloic-II acid hydrochloride treated with phosphorus oxychloride and l-penillamine-II hydrochloride isolated in the usual way. Similarly, d-penicillamine hydrochloride and phenylacetylamino diethyl acetal yield d-penilloic-II acid hydrochloride, which cyclises in phosphorus oxychloride to give eventually d-penillamine-II hydrochloride.  Specification 584,918 is referred to.