Synthesis of HR 916 B: The First Technically Feasible Route to the 1-(Pivaloyloxy)ethyl Esters of Cephalosporins

✍ Scribed by Fleischmann, Klaus ;Adam, Friedhelm ;Dürckheimer, Walter ;Hertzsch, Winfried ;Hörlein, Rolf ;Jendralla, Heiner ;Wollmann, Theo ;Lefebvre, Christian ;Mackiewicz, Philippe ;Roul, Jean-Michel

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 892 KB
• Volume: 1996
• Category: Article
• ISSN: 0947-3440
• DOI: 10.1002/jlac.199619961106

✦ Synopsis

Abstract

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).