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Synthesis of piperacillin with low impurity content using a new three-feed membrane dispersion microreactor
Chemical Engineering Journal ( IF 15.1 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.cej.2020.124178
Yu Xie , Guoming Huang , Yujun Wang , Zhengren Yan , Xin Wang , Juan Huang , Mingtang Gao , Weiyang Fei , Guangsheng Luo

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.



中文翻译:

新型三进料膜分散微反应器合成低杂质哌拉西林

哌拉西林的合成对混合效果和系统的pH值非常敏感。由于使用传统反应器的氯化氨苄法中微混合效果差且pH控制不精确,因此哌拉西林的杂质含量不符合生产标准。因此,提出了一种新型的三进料膜分散微反应器,并用于合成哌拉西林,首先将氨苄西林与4-乙基-2,3-二氧代-1-哌嗪羰基氯(EDPC)混合,然后与氨水混合。快速激烈的混合条件。氨苄西林的循环过程和EDPC的缓慢添加也有助于稳定pH值。氨进料和EDPC进料之间的距离,pH,反应温度,EDPC比,研究了循环流速对哌拉西林和杂质含量的影响。在最佳条件下,在微型反应器中,缩合溶液中的哌拉西林含量在10分钟内达到约94.90%,而传统罐中在60分钟内仅达到91.06%。更重要的是,关键杂质D和E的含量分别从0.340%降低到0.080%,和从0.176%降低到0.035%。进行后续工艺以获得最终的哌拉西林产物,其平均收率约为93.99%;纯度一般在99.7%以上。杂质D的含量一般小于0.1%,杂质E的含量小于0.05%,符合药典和抗生素杂质的规定。在微型反应器的最佳条件下,在10分钟内90%的含量,但传统反应釜中60分钟内的含量仅达到91.06%;更重要的是,关键杂质D和E的含量分别从0.340%降低到0.080%,和从0.176%降低到0.035%。进行后续工艺以获得最终的哌拉西林产物,其平均收率约为93.99%;纯度一般在99.7%以上。杂质D的含量一般小于0.1%,杂质E的含量小于0.05%,符合药典和抗生素杂质的规定。在微型反应器的最佳条件下,在10分钟内90%的含量,但传统反应釜中60分钟内的含量仅达到91.06%;更重要的是,关键杂质D和E的含量分别从0.340%降低到0.080%,和从0.176%降低到0.035%。进行后续工艺以获得最终的哌拉西林产物,其平均收率约为93.99%;纯度一般在99.7%以上。杂质D的含量一般小于0.1%,杂质E的含量小于0.05%,符合药典和抗生素杂质的规定。分别。进行后续工艺以获得最终的哌拉西林产物,其平均收率约为93.99%;纯度一般在99.7%以上。杂质D的含量一般小于0.1%,杂质E的含量小于0.05%,符合药典和抗生素杂质的规定。分别。进行后续工艺以获得最终的哌拉西林产物,其平均收率约为93.99%;纯度一般在99.7%以上。杂质D的含量一般小于0.1%,杂质E的含量小于0.05%,符合药典和抗生素杂质的规定。

更新日期:2020-01-22
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