A NOVEL INTERMEDIATE AND ITS USE IN THE PREPARATION OF CEPHEMS (01-Oct-2009)

Abstract

The present disclosure relates to a novel intermediate, S-(5-methyl-1,3,4-thiadiazol-2-yl) (2Z)-[(acetyloxy)imino](2-amino-1,3-thiazol-4-yl)ethanethioate(acetyloxy BAEM), used in the preparation of  cephems; particularly cefdinir.  The disclosure also relates to a process for the preparation of cephems by said intermediate.

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Cefdinir, cefpodoxime proxetil and cefotaxime all are third generation cephalosporin antibiotics which possess broader antibacterial spectrum for both gram positive and gram negative bacteria, particularly against staphylococci and straptococci and a high stability against various beta-lactamases.

Cefpodoxime proxetil and cefotaxime have been described for the first time in the published German application DE 2556736 (corresponding to U.S. Patent No. 5,583,216) whereas cefdinir was first described in U.S. Patent No. 4,559,334.

Literature reports activation of carboxylic group of the side chain used for the preparation of various cephalosporins in the form of their acid chlorides, anhydrides, esters, amide which requires protection and deprotection of NH2 group of the thiazole ring.

U.S. Patent Nos. 5,856,502 and 5,037,988 relates to activation of carboxylic group to acid chloride by SO₂Cl₂ followed by usage of harmful chemicals like benzene and toluene.

U.S. Patent Nos. 4,576,749 and 4,548,748 relates to activation of carboxylic group in the side chain involving 1-hydroxybenzotriazole or mercaptobenzothiazole in the presence of dicyclohexylcarbidiimide (DCC) which is reacted to cephem moiety to produce cephalosporins.

U.S. Patent No. 4,767,852 discloses the use of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) for acylating cephem moiety.

U.S. Patent No. 4,559,334 discloses the synthesis of crystalline cefdinir involving benzhydryl 7-(4-bromoacetaamido)3-vinyl-3-cephem-4-carboxylate with thoiurea in dichloromethane and acetic acid followed by cleavage of benzyhydryl group with trifluoroacetic acid followed by isolation of cefdinir involving lyophilization.

U.S. Patent No. 4, 935,507 relates to the reaction of  carboxyl-protected 7-amino-3-vinyl-3-cephem-4-carboxylic acid with butanedioic acid chloride followed by nitrosation and condensation with thiourea, removal of carboxy protective group.

U. S. Patent No. 6,093,814 discloses the synthesis of cefdinir involving dimethylacetamide solvate of a tosyl salt of cefdinir followed by crystallizing of the said intermediate with large amounts of diethylether.

WO 98/45299 discloses the purification and preparation of cefdinir involving cefdinir dicyclohexylamine salt, involving solvent anti-solvent system.

WO 02/098884 describes preparation of cefdinir involving trea...