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Synthesis 1992; 1992(11): 1160-1164
DOI: 10.1055/s-1992-26326
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Synthesis of a Dual-Action Cephalosporin: A Novel Approach to 3-Acyloxymethyl-3- cephems

Masami Okabe* , Ruen-Chu Sun
  • *Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA
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Publication Date:
17 September 2002 (online)

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A practical synthesis of the dual-action cephalosporin 5 from 7-aminocephalosporanic acid (7-ACA), S-benzothiazol-2-yl (2-amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM), and fleroxacin [6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazi-nyl)-4-oxo-3-quinolinecarboxylic acid, 3] is described. Tritylated MAEM prepared in situ was coupled with 7-ACA in dichloromethane followed by hydrolysis of the acetate group to afford the 3-hydroxymethyl-3-cephem 2. The direct acylation of 2, which has an unprotected 4-carboxy group, with activated esters of 3 gave mixtures of the desired ester A (4) and the lactone B. The ratio of these two products was found to depend on the nature of the leaving group of the activated ester used, with the one prepared from cyclohexyl chloroformate favoring the formation of 4. Ester 4 was isolated in more than 50% overall yield from 7-ACA. Removal of the trityl group afforded the dual- action cephalosporin 5.