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

✍ Scribed by Defoßa, Elisabeth ;Fischer, Gerd ;Gerlach, Uwe ;Hörlein, Rolf ;Isert, Dieter ;Krass, Norbert ;Lattrell, Rudolf ;Stache, Ulrich ;Wollmann, Theo

Publisher
John Wiley and Sons
Year
1996
Tongue
English
Weight
774 KB
Volume
1996
Category
Article
ISSN
0947-3440

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✦ Synopsis

Abstract

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.

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Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1-(Pivaloyloxy)ethyl Esters of Cephalosporins. -Diastereomerically pure HR 916 K (VI), the 1(S)-pivaloyloxyethyl prodrug ester of the cephalosporin cefdaloxime, is synthesized and separated from the (R) diastereomer as HCl s

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## 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 nucleoph