Synthesis of piperacillin with low impurity content using a new three-feed membrane dispersion microreactor

Abstract

The synthesis of piperacillin is very sensitive to the mixing effect and the pH of the system. Because of poor micro-mixing and imprecise pH control in the ampicillin chloride method using the traditional reactor, the impurity content of piperacillin does not meet the production standard. Therefore, a novel three-feed membrane dispersion microreactor was proposed and used to synthesize piperacillin, in which ampicillin was first mixed with 4-ethyl-2,3-dioxo-1-piperazine carbonyl chloride (EDPC) and then mixed with ammonia water under rapid and intense mixing conditions. The process of ampicillin circulation and slow addition of the EDPC also contributed to stabilizing the pH value. The effects of the distance between the ammonia feed and the EDPC feed, pH, reaction temperature, EDPC ratio, and circulation flow rate on the content of piperacillin and impurities were investigated. The piperacillin content of the condensation solution reached ~94.90% within 10 min under the optimal conditions in the microreactor, but the content only reached 91.06% in 60 min in the traditional tank; more importantly, the content of the key impurities D and E decreased from 0.340% to 0.080%, and 0.176% to 0.035%, respectively. Subsequent processes were carried out to obtain the final piperacillin product, where the average yield was around 93.99%; the purity was generally above 99.7%; the content of impurity D was generally less than 0.1%, and the content of impurity E was less than 0.05%, meeting the guidelines of the pharmacopoeia and antibiotic impurity.