Cefditoren has low toxicity to mammals but exhibits a very broad antibacterial spectrum against positive-bacteria and gram-negative bacteria. Cefditoren is known to be a highly excellent therapeutic agent, which has been extensively utilized for the therapeutic treatments and preventive treatments of bacterial infections caused, by a variety of gram-positive bacteria and gram-negative bacteria.
Originally Cefditoren was disclosed in U.S. Pat. No. 4,839,350. This patent also discloses various processes for the preparation of Cefditoren.
U.S. Pat. Nos. 5,616,703 and 6,235,897 discloses a process for the depletion of 7-amino-3-[(E)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid in Z/E mixtures of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid a) by subjecting an amine salt of a Z/E mixture of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid to crystallization and converting this amine salt into 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, or b) by subjecting the Z/E mixture to chromatography.
U.S. Pat. No. 6,288,233 discloses a process for the preparation of Cefditoren by condensing Wittig salt of cephem moiety with thiazole-5-carbaldehyde in a mixture of chlorinated hydrocarbon and lower alkanol medium.
Chem. Pharm. Bull. 39, (1991), 2433 discloses a process which involves conversion of GCLE (II) into Wittig salt, Wittig reaction with 5-formyl-4-methylthiazole, separation of isomer by fractional crystallization followed by column chromatography, deprotection to get free amine, reaction with protected MAEM followed by deprotection to get free acid (I). The E/Z isomer separation involves column chromatography hence yield is less.
wherein PMP denotes p-methoxy phenyl
The foregoing processes are associated with many problems such as poor yield and quality, difficult to commercialization, impurity and percentage of E isomer content is high. Hence there is a need to develop a process, which is easy to commercialize, and which yields good quality as well as quantity. We focused our research to find a process and finally achieved identifying a clean process for producing the title compound of the invention, which contains less percentage of E isomer.
USPTO Backgrounds
USPTO Backgrounds