Synthesis method of ceftibuten 7[beta]-site side chain intermediate

Abstract

The invention discloses a synthesis method of a ceftibuten 7[beta]-site side chain intermediate. The method comprises the following steps enabling 2-(2-carbobenzoxyaminothiazole-4-yl)-2-pentenedioic acid to react with an alkaline compound to prepare a monosodium salt of the 2-(2-carbobenzoxyaminothiazole-4-yl)-2-pentenedioic acid; then performing a reaction with 1-bromo-3-methyl-2-butylene to prepare the ceftibuten 7[beta]-site side chain. The synthesis method is simple to operate, high in controllability, short in technological process, high in yield and suitable for popularization and application.

Description

technical field [0001] The invention designs a method for synthesizing a key intermediate of cephalosporin antibiotics, in particular to a method for synthesizing a side chain intermediate at the 7β position of ceftibuten. Background technique [0002] Ceftibuten, English name Ceftibuten (other names are ceftibutan, 7432-5, etc.), is the third generation broad-spectrum oral cephalosporin created by Shionogi Company in Japan. The chemical name is 7β-[2-(2-amino-4-thiazolyl)-4-carboxy-2-(Z)-butenamido]-3-cephem-2-carboxylic acid. This product is a third-generation oral cephalosporin with broad-spectrum antibacterial activity, strong antibacterial effect on most Gram-negative bacilli and some positive cocci, highly stable to plasmid-mediated lactamase, and antibiotic After Effects. [0003] Intermediate 2-(2-benzyloxycarbonylaminothiazol-4-yl)-5-(3-methyl-buteneoxycarbonyl)-2-pentenoic acid (hereinafter referred to as Intermediate-1) is the product of ceftibuten The difficul...

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Problems solved by technology

[0004] U.S. Patent No. 4,634,697 discloses a method for synthesizing a side chain intermediate of ceftibuten. This method uses a variety of highly toxic, corrosive, flammable and explosive raw materials, and the yield of the entire process is extremely unstable, which is difficult to achieve industrially.

[0005] Beijing Institute of Technology doctoral dissertation "Total Synthesis of Ceftibuten and Synthesis of 2,3-Cyclopentenopyridine" also mentioned a preparation process of ceftibuten side chain. Ester restrictions, high production costs, and thiourea used in cyclization, contact may cause great harm to the human body

[0006] Patent CN101824004B belongs to a new process, which uses 2-aminothiazole acetic acid as the starting material, and is formed through carboxyl protection, amino protection, methylolation, witing reaction, and monoesterification. This process avoids the use of 3-methoxyacrylic acid methyl ester, but the content of the product obtained during the synthesis process is low, and the HPLC method detects that the content is about 85%, which has a great impact on the later purification yield. On the other hand, the incompletely reacted 2-(2-benzyloxy Carbonylaminothiazol-4-yl)-2-pentaconate exists in the green leaves that contain more other substances in the later stage and is difficult to recover, resulting in a great waste

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