Method for preparing tebipenem

Abstract

The invention relates to a method for preparing carbapenem type antibiotic tebipenem. The method comprises the following steps of: carrying out catalytic hydrogenation on p-nitrobenzyl tebipenem under the presence of an organic alkali reagent and a metal catalyst (such as palladium / carbon) to remove p-nitrobenzyl ester to obtain the tebipenem, and further esterifying the tebipenem to obtain tebipenem ester. The method disclosed by the invention has the advantages of: (1) solving instability of the p-nitrobenzyl tebipenem in a catalytic hydrogenation protective group removal process and improving the yield and purity; and (2) simplifying operation steps, saving troubles of post-treatment and improving efficiency.

Description

technical field [0001] The invention belongs to the field of chemistry or pharmaceutical chemistry, and specifically relates to a method for preparing tipipenem, and further relates to a method for obtaining tipipenem ester through esterification of tipipenem. technical background [0002] Tebipenem pivoxil (L-084) is the first oral β-methylcarbapenem antibiotic product developed by Japan’s Meiji Seika Company. This product is used for the treatment of Streptococcus pneumoniae infection. , including persistent otitis media and bacterial pneumonia, especially against Gram-positive bacteria such as Streptococcus pneumoniae, especially for children with acquired pneumonia, and has obvious advantages over other penem antibiotics. This product was approved and recommended in Japan in April 2009 for the treatment of ENT and upper respiratory tract infections in pediatric patients. [0003] [0004] tipipenem [0005] According to the existing literature reports, there are two...

AI Technical Summary

Problems solved by technology

The method has the following problems: the zinc solution after reduction is an emulsion and a large amount of inorganic salts cannot be removed, and the formula (I) compound is difficult to separate out crystals from water, which is not convenient for the purification of the product; the reaction conditions are not suitable for the reaction substrate and the product. Stable, will cause β-lactam ring-opening by-products, resulting in increased impurities; post-treatment requires column chromatography to separate and purify, increasing the difficulty of operation, resulting in reduced yield and quality, and difficult to achieve industrial production

This method overcomes the shortcoming that post-treatment is not easy to purify brought by the zinc reduction hydrolysis operation in EP0632039, simplifies the steps of post-treatment operation, and reduces the speed that the product is degraded, but this method also has the following shortcoming: use sodium bicarbonate as alkalizing reagent , the hydrogenolysis is slow and incomplete, and the reaction needs to be prolonged for complete reaction, which will easily lead to the degradation of the product in an alkaline environment and affect the yield and quality of the product; in the post-treatment process, it is necessary to add hydrochloric acid to neutralize and then crystallize, which will easily lead to Exceeding the standard of inorganic salt will also cause the degradation and damage of the product. These degraded impurities will affect the subsequent reaction and increase the difficulty of purification of the final product, directly affecting the yield of the subsequent reaction

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