Cefdaloxime pentexil tosilate

HR 916 K (5), the 1‐(S)‐(pivaloyloxy)ethyl prodrug ester of the cephalosporin cefdaloxime, exhibits a significantly higher oral bioavailability than the 1‐(R) diastereomer HR 916 J. An efficient synthesis of HR 916 K was developed. The separation of the diastereomers was achieved by precipitation of the 1‐(R)‐hydrochloride 9 followed by crystallization of the 1‐(S)‐amine 10 (de > 96%). The 1‐(R) diastereomer 9 was recycled by acidic saponification or enzymatic cleavage to AMCA (7). The amine 10 was acylated with mercaptobenzothiazole thioesters or mixed anhydrides, prepared from carboxylic acids 13 and 14, in almost quantitative yield. Deprotection of the oxime and formation of the tosylate proceeded in one step. Using thioester 18, we obtained HR 916 K (5) from AMCA (7) in 42% yield.

An efficient synthesis of HR 916 B (4), the orally active 1‐(RS)‐(pivaloyloxy)ethyl prodrug ester of the cephalosporin cefdaloxime, was developed and applied on a multi‐kg scale. AMCA (8) was prepared by exchange of the acetoxy group of fermentation product ACA (7) with the nucleophile methanol under acidic conditions. Its 7‐amino group was acylated with mixed anhydride 14 to give 15. Carboxylic acid 15 was esterified with iodohydrin ester 27 or bromohydrin ester 30, respectively, to provide the acylal 16. Simultaneous removal of both the amino‐ and the oximo‐protecting group furnished the prodrug HR 916 3, which was purified and stabilized by precipitation of its tosylate salt 4. The overall yield of 4 (ratio 5/6 = 0.65) was 39% relative to AMCA (8) (four steps), 15% relative to ACA (7) (five steps).