Benzylpenicillenic acid as an intermediate in the synthesis of benzylpenicillin.

During the war several English and American laboratories participated in a study of the structure and synthesis of penicillin (1, 2). In this work it was noted that when the methyl ester of benzylpenicillin (I) (see Fig. 1) was treated with mercuric chloride in ether solution and the resulting mercury derivative (II) was decomposed with hydrogen sulfide, a neutral, amorphous product was obtained. This crude product possessed an absorption peak in the ultraviolet at 320 rnp (E M = 13,700)l and was degraded by sodium hydroxide to the sodium salt of 2-benzyl-4-hydroxymethylene5(4)-oxazolone. For these and other reasons the product was assigned structure (III) and was given the trivial name methyl n-benzylpenicillenate (3). After the close of the war, studies were continued in this Laboratory on the synthesis and the mechanism of synthesis of benzylpenicillin from Dpenicillamine hydrochloride (V) and 2-benzyl-4-methoxymethylene-5(4)oxazolone (IV) (4, 5). It was found that when the two compounds were allowed to react in pyridine containing triethylamine, a biologically inactive, amorphous product was obtained. However, when this product was heated in pyridine containing pyridinium chloride, benzylpenicillin was formed in small yield. The intermediate product possessed an ultraviolet absorption spectrum similar to that described for natural methyl D-benzylpenicillenate (III) .’ So far attempts to isolate the intermediate compound in crystalline form have not been successful. During the course of fractionation studies on this product, the formation of D-benzylpenillic acid (VI) was encountered (6). This n-benzylpenillic acid was identical with that formed by rearrangement of benzylpenicillin.