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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-Aminopenicillamic Acid

DOI: 10.1039/P19940000179

Source and publish data:

Journal of the Chemical Society. Perkin transactions I p. 179 - 188 (1994)

Update date:2022-08-04

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Authors:

Osborne, Neal F.Osborne, Neal F.

Atkins, Richard J.Atkins, Richard J.

Broom, Nigel J. P.Broom, Nigel J. P.

Coulton, StevenCoulton, Steven

Harbridge, John B.Harbridge, John B.

et al.et al.

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Article abstract of DOI:10.1039/P19940000179

(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 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 phosphine-mediated carbonyl-carbonyl coupling reaction.Sequential tretment of bromopenem 17 with lithium diphenylamide, 1-methyl-1,2,3-triazole-4-carbaldehyde, and acetic anhydride gave a diastereomeric mixture of acylated bromohydrins 32; reductive elimination of this mixture afforded a separable mixture of (Z)- and (E)-triazolylmethylenepenem 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-heterocyclilmethylene 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.

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Product name:p-methoxybenzyl-6-α-bromopenicillanate

Cas No:96572-55-3

96572-55-3

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