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
| Autor: | John Barry Harbridge, Nigel J. P. Broom, Graham Walker, Richard J. Atkins, Steven Coulton, Neal Frederick Osborne, Irene Stirling-François, Michael Anthony Harris |
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| Rok vydání: | 1994 |
| Předmět: | |
| Zdroj: | J. Chem. Soc., Perkin Trans. 1. :179-188 |
| ISSN: | 1364-5463 0300-922X |
| DOI: | 10.1039/p19940000179 |
| Popis: | (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. |
| Databáze: | OpenAIRE |
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