The Process Improvement Of Pipemidic Acid

Pipemidic acid which belongs to quinolones has exhibited antibacterial activity against gram negative bacteria such as pyocyanin, escherichia coli, proteobacteria and Klebsiella pnenmoniae. It is more active than Nalidixic acid, Piromidic acid, Cephalexin IV and Ampicilin. It is also effective on Gram positive bacteria. In addition, pipemidic acid did not show toxicity, side effects and drug resistance compared with other antimicrobial drugs. Therefore, this drug has been widely used for treatment of surgical infection, gastrointestinal tract infection, gynecology and obstetrics infection, et al. There are two synthetic routes for pipemidic acid according to the two different starting material 2-methyl sulphide-4-aminopyrimidin and 4-chloro pyrimidine-5-carboxylic acid ethyl ester derivatives. Xinhua pharmaceutical company has a long history to synthesize pipemidic acid using the 4-chloro pyrimidine-5-carboxylic acid ethyl ester.We analyzed the factors which might influence the quality of products and confirmed the structure of impurities. According to the properties of the impurities, we modified the process of the condensation, hydrolysis and purification, which get rid of the problem in quality of key intermediate. And then, we reduced the temperature of crude product filtration and used sodium methoxide or potassium methoxide as cyclization reagent. The results showed that yield of product up to 68.6% or 65.17%, respectively. However, the reaction gave additional impurities which needed to be removed afterwards. In addition, the decoloring temperature was studied in our research and the result suggests that 65-70℃would be better than 90℃. Considering the price of acetic acid increased sharply, the cheaper reagent, sulfuric acid, was tried to use in acidification. The preliminary studies showed that the clarity of the products conform to our demand after removing SO42- residues,.