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Synthesis 2012(2): 207-214  
DOI: 10.1055/s-0031-1289654
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Synthesis of Cefcapene Pivoxil

Jian-An Jianga, Jiao-Jiao Zhaia, Xin-Hong Yua, Xin Teng*b, Ya-Fei Ji*a
a School of Pharmacy, East China University of Science and Technology, Campus P.O. Box 363, 130 Meilong Road, Shanghai 200237, P. R. of China
Fax: +86(21)64253314; e-Mail: jyf@ecust.edu.cn;
b School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, P. R. of China
e-Mail: tengxin@ecust.edu.cn;
Further Information

Publication History

Received 12 October 2011
Publication Date:
22 December 2011 (online)

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Abstract

Cefcapene pivoxil monohydrochloride monohydrate, a broad spectrum third-generation cephalosporin for oral administration, was prepared by reacting three centers of 7β-amino-3-(hydroxymethyl)cephalosporinic acid (7-HACA), derived from 7β-aminocephalosporanic acid. The coupling of 7-HACA and (Z)-2-[2-(Boc-amino)thiazol-4-yl]pent-2-enoic acid, followed by carbamylation with chlorosulfonyl isocyanate, and precipitation with diisopropylamine gave the key intermediate, in which thiazole side chain and carbamoyl group had been introduced into the 7-amino and 3-hydroxymethyl groups of 7-HACA, respectively, in a continuous procedure. Afterwards, the intermediate was esterified with pivaloyloxymethyl iodide to complete the modification of the C4 carboxy group affording Boc-cefcapene pivoxil, from which the desired product was finally obtained by an economical Boc removal and successive formation of the hydrochloride in 36% overall yield on a decagram scale. This synthesis promises an easy entry to cefcapene pivoxil monohydrochloride monohydrate with convenient manipulation, simple isolation, and good yields; it is of potential value for production on an industrial scale.

Key words

antibiotics - cephalosporins - cefcapene pivoxil - 7-ACA - carbamylation - semisynthesis

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The Japanese Pharmacopoeia Fifteenth Edition at http://www.drugfuture.com/Pharmacopoeia/JP15/ JP15e.html.