Synthesis technology of cefoxitin acid

Abstract

The invention provides a novel synthesis method of cefoxitin acid. Cefoxitin acid is used as a raw material for synthesizing cefoxitin sodium and belongs to second-generation cephalosporin. The cefoxitin acid has balanced antibacterial spectra and has a strong antibacterial effect on gram-negative bacteria. Due to the existence of 7alpha methoxy in the cefoxitin acid, the hydrolysis action of the cefoxitin acid on beta-lactamase can be reduced greatly, so that the beta-lactamase can exist stably in the cefoxitin acid. In the invention, 3-deacetylase cefoxitin acid which is an intermediate is produced by adopting an enzyme process through two-step continuous reaction, materials react in a mild reaction condition, and the process is simple and is convenient to operate. By adopting the novel synthesis method, time and labor can be saved, and the yield and quality of the product can be improved. Because the two-step reaction is carried out in a water phase at room temperature, the consumption of energy and the discharge of organic wastewater can be reduced greatly. The novel synthesis method meets the requirements of large-scale industrial production.

Description

Technical field [0001] The invention relates to a preparation method of cephalosporin antibiotics, in particular to a preparation method of cefoxitin acid, belonging to the field of pharmaceutical chemical synthesis. Background technique [0002] Cefoxitin, chemical name: (6R, 7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-[2-(2-thiazolyl)ethyl Amido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, its molecular formula is C 16 H 17 N 3 O 7 S 2 , The molecular weight is 427.46, and the chemical structure is shown in (I): [0003] [0004] Cefoxitin acid is the raw material for the synthesis of cefoxitin sodium. Cefoxitin sodium is a cephalosporin antibiotic developed by Merck in the United States. It belongs to the second generation of cephalosporins. It has a balanced antibacterial spectrum, especially for Gram-negative bacteria. Strong antibacterial effect, due to the presence of the methoxy group at the 7α position, can greatly reduce the hydrolysis of β-lactamase, so it is ...

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Problems solved by technology

[0006] 1) U.S. Patent US4297488 reports the synthesis of cefoxitin using cephamycin C as a raw material. The process is cumbersome, the yield is low, the cost is high, and the fermentation level of raw material cefoxitin C is low and difficult to obtain, so it has no industrial value

[0007] 2) Chinese patent CN101007812A has reported that with 7-MAC (methoxy cephalosporin) as raw material through 2-thiophene acetylation reaction, hydrolysis reaction and carbamoylation reaction obtain cefoxitin, because the price of 7-MAC is relatively Expensive, the process cost is not dominant

[0008] 3) Chinese patent CN101555252A reported that cefoxitin was obtained from 7-ACA (7-aminocephalosporanic acid) through acylation, methoxylation, hydrolysis and carbamoylation. The main method of industrial production of cefoxitin, but the operation is complicated, the yield is low, and the cost is high

[0009] Due to the starting materials in the existing route, one class is easy to get but complex structure cephamycin C, and the other is simple in structure but difficult to obtain various cephalosporanic acid derivatives; the process method is also relatively loaded down with trivial details, The yield is low and the operation is complicated. Therefore, there is an urgent need for a synthetic process with low raw material cost, simple process route, strong operability, high yield and low cost.

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