Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1-(Pivaloyloxy)ethyl Esters of Cephalosporins

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.