Method for synthesizing faropenem sodium

Abstract

The invention provides a method for synthesizing faropenem sodium. According to the method, oxalic acid chloride p-nitrobenzyl ester is used for replacing allyloxy oxalyl chloride in a conventional process, and thus the generation of polymer impurities is effectively prevented, and the raw material conversion rate and the product yield are increased; by adopting a method of catalytic hydrogenation under an acidic condition, silylation protection groups and p-nitrobenzyl ester protection groups are removed, organophosphorus impurities which are difficult to treat are effectively prevented, the separation and purification of products are facilitated, the maneuverability is improved, and the industrialized production is facilitated.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of faropenem sodium. Background technique [0002] Faropenem sodium is the first penem antibiotic developed by Japan's Suntory Company and launched in 1997. It is similar to several carbapenem antibiotics that have been on the market. It has a broad antibacterial spectrum and strong antibacterial activity. β-lactamase is stable, and it also has good effects on extended-spectrum β-lactamase-producing bacteria, Citrobacter, enterococcus and anaerobic bacteria. It is the world's first orally effective penem antibiotic that is stable to β-lactamase so far. Its structural formula is as follows: [0003] [0004] There are many reports about the preparation method of faropenem sodium, mainly as follows: [0005] 1. The method reported in J. Antibiotics 1988,41,1685, see the following reaction formula: [0006] [0007] Use 4-AA and trityl mercaptan to perform acyl s...

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Problems solved by technology

[0007] use 4-AA and trityl mercaptan to carry out acyl substitution reaction under alkaline conditions to obtain the azetidinone protected by thiotrityl group, and then When tetrahydrofuran-2-formyl chloride is connected with lactam, silver nitrate is used as a condensation agent, but silver nitrate is expensive and the cost is too high, and the silver chloride generated at the same time is not easy to filter and is not suitable for large-scale production

[0008]2. U.S. Patent US4997829 reports the classic preparation method: acyl substitution reaction with (R)-tetrahydrofuran-2-thiocarboxylic acid to generate thioester, and then condensation , chlorine substitution, intramolecular Witting cyclization reaction, removal of hydroxyl protecting group and carboxyl protecting group to obtain the product, the yield of this synthetic route is very low, and the side chain is a thio compound, the smell is extremely smelly, and the preparation is complicated, which is harmful to the human body and The environment has certain hazards

[0013] However, in the final operation, the above method involves the use of heavy metal palladium acetate and other salt compounds and triphenylphosphine as the de-allyl group Protective reagents, metal palladium reagents are expensive, and triphenylphosphine is difficult to remove in the final step, which increases the difficulty of operation and affects product quality

At the same time, using allyloxy group as a protecting group is easy to produce a double bond olefin polymer impurity, which affects product quality and reduces yield

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