Ceftibuten: Development of a Commercial Process Based on Cephalosporin C. Part III. Process for the Conversion of 3-Exomethylene-7(R)-glutaroylaminocepham-4-carboxylic Acid 1(S)-Oxide to Ceftibuten

Abstract

The foregoing papers (Bernasconi, E.; Lee, J.; Roletto, J.; Sogli, L.; Walker, D. Org. Process Res. Dev. 2002, 6, 152 and Bernasconi, E.; Genders, D.; Lee, J.; Longoni, D.; Martin, C. R.; Menon, V.; Roletto, J.; Sogli, L.; Walker, D.; Zappi, G.; Zelenay, P.; Zhang, H. Org. Process Res. Dev. 2002, 6, 158) describe a high-yielding, all-aqueous process for the preparation of 3-exomethylene-7(R)-glutaroylaminocepham-4-carboxylic acid 1(S)-oxide (3) from fermented cephalosporin C broth via enzyme transformations and electrochemical reduction without isolation of any precursors. In this paper we describe the efficient recovery of 3 from aqueous solution, by extractive esterification employing diphenyldiazomethane, and the conversion of the obtained bis(diphenylmethyl) ester (4) into intermediates both for Ceftibuten (1) and cefaclor (8). Several routes to the key Ceftibuten building block, diphenylmethyl 7(R)-aminoceph-3-em-4-carboxylate (6) are described. This key building block is acylated, deblocked, and pur...