Synthesis of (5R)-(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid, a potent broad spectrum β-lactamase inhibitor, from 6-aminopenicillanic acid

Abstract

(5R)-(Z)-6-(1-Methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid 34(BRL 42715) has been prepared from 6-aminopenicillanic acid 4(6-APA) by a short, stereoselective and efficient route via the novel intermediate, p-methoxybenzyl (5R, 6S)-6-bromopenem-3-carboxylate 17.

Elaboration of 6-APA 4 to the azetidinone disulfide 10 by established methodology, followed by reductive formylation provided the crystalline C-4 formylthio-azetidinone derivative 29. Cyclization of the oxalimide 28, obtained by ozonolysis of the formylthio derivative 29, to the crystalline 6α-bromopenem ester 17 was effected by way of the phosphite-mediated carbonyl–carbonyl coupling reaction.

Sequential treatment of bromopenem 17 with lithium diphenylamide, 1-methyl-1,2,3-triazole-4-carbaldehyde, and acetic anhydride gave a diastereoisomeric mixture of acylated bromohydrins 32; reductive elimination of this mixture afforded a separable mixture of (Z)- and (E)-triazolylmethylene penem esters, 33 and 35 respectively. Lewis acid-mediated deprotection of ester 33 provided (5R)(Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)penem-3-carboxylic acid 34(BRL 42715) as a crystalline sodium salt monohydrate.

The 6-heterocyclylmethylene penems, represented by BRL 42715, are potent inhibitors of bacterial β-lactamases and their combination with an appropriate penicillin or cephalosporin results in good synergistic activity against a broad range of β-lactamase-producing bacteria.