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NOVEL INTERMEDIATE FOR THE PREPARATION OF CEPHALOSPORIN

IP.com Disclosure Number: IPCOM000175754D
Publication Date: 2008-Oct-22
Document File: 11 page(s) / 67K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure relates to a compound, dicyclohexylamine salt of 4-bromo-2-methoxyimino-3-oxo butyric acid, which is a useful intermediate for preparing cephem compounds such as cefpodoxime proxetil or cefotaxime. The disclosure also relates to a process for its preparation.

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NOVEL INTERMEDIATE FOR THE PREPARATION OF CEPHALOSPORIN

Abstract

The present disclosure relates to a compound, dicyclohexylamine salt of 4-bromo-2-methoxyimino-3-oxo butyric acid, which is a useful intermediate for preparing cephem compounds such as cefpodoxime proxetil or cefotaxime.  The disclosure also relates to a process for its preparation.

Cefpodoxime Proxetil and Cefotaxime are third generation cephalosporin antibiotics which possess broader antibacterial spectrum for both gram positive and gram negative bacteria.  The activity in cefpodoxime proxetil is primarily due to cefpodoxime acid which is generated easily in vivo by hydrolysis.

U.S. Patent No. 4,152,432 claims cefotaxime generically and specifically along with its pharmaceutically acceptable composition.  U.S. Patent No. 4,486,425 claims cefodoxime proxetil specifically and U.S. Patent No. 4,716,158 claims cefodoxime proxetil generically.  They also discloses a process involving acylation of 7-aminocephalosporanic acid or its ester derivative with reactive derivative of iminothiazolyl acetic acid such as acid chloride, anhydride, amides and azides which is protected at the amino group of the thiazolyl ring and formed insitu by reaction of isobutylchloroformate and dicyclohexylcarbodiimide.  

Generally, two methods have been described in the prior art for preparing cephem compounds.  First method involves amidification of the 7-amino function of the corresponding 3-(un)substituted cephalosporin derivative with 2-(2-aminothiazol-4-yl)-2-oxyimino acetic acid derivative.  The other method involves amidification with 4-halo-2-oxyimino butyric acid derivative to give 7-substituted cephalosporin addendum, which can be further reacted with thiourea to form cephem compounds

Some of the prior art references describing above methods for the synthesis of cephem compounds are as cited below:

U.S. Patent No. 4,767,852 discloses a process for production of cephems by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM).

U.S. Patent Nos. 4,576,749 and 4,548,748 describe preparation of cephem antibiotics involving activation of imino ester with 1-hydroxybenzotriazole (HOBT) or 2-mercaptobenzothiazole (MBT) in presence of dicyclohexylcarbodiimide.

U.S. Patent No. 6,388,070 describes acylation of silylated cephem compound with thioester derivatives of thiazolyl acetic acid.

U.S. Patent No. 5,739,346 describes a process for the synthesis of β-lactam derivatives including cefotaxime involving activation of thiazolyl oxyimino acetic acid derivative with N,N-dimethyl formiminium chloride chlorosulfate.

U.S. Patent No. 4,298,529 discloses a process for the preparation of cephalosporins involving reaction of silylated cephem compound with activated imino-3-oxobutyric acid.

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