文献类型：期刊文献

英文题名：Enzymatic Preparation of the Chiral (S)-Sulfoxide Drug Esomeprazole at Pilot-Scale Levels

作者：Xu, Na[1];Zhu, Jun[1];Wu, Yin-Qi[1];Zhang, Yan[1];Xia, Jian-Ye[1];Zhao, Qian[3];Lin, Guo-Qiang[3];Yu, Hui-Lei[1,2];Xu, Jian-He[1,2]

机构：[1]East China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai 200237, Peoples R China;[3]Jiangsu Aosaikang Pharmaceut Co Ltd, Jiangsu Key Lab Chiral Drug Dev, Nanjing 211112, Peoples R China

年份：2020

卷号：24

期号：6

起止页码：1124

外文期刊名：ORGANIC PROCESS RESEARCH & DEVELOPMENT

收录：;EI(收录号：20202908933358);WOS:【SCI-EXPANDED(收录号:WOS:000543672300022)】；

基金：The work was financially supported by the National Natural Science Foundation of China (nos. 21922804, 21871085 & 21536004), the National Key R&D Program of China (no. 2019YFA09005000), and the Fundamental Research Funds for Central Universities (no. 22221818014). We thank classmates in the State Key Laboratory of Bioreactor Engineering, whose names are Yu-Cong Zheng, Feng Liu, Shi-Miao Ren, Peng Zhao, Ya-Jing Li, and Xiao-Long Qian, for contributing to this work.

语种：英文

外文关键词：prazole sulfide monooxygenase; esomeprazole; asymmetric oxidation; oxygen mass transfer; reaction regulation

摘要：Esomeprazole is the most popular proton pump inhibitor (PPI) for treating gastroesophageal reflux disease. Enzymatic asymmetric sulfoxidation is a green approach to produce chiral sulfoxides. In this report, we focused on optimizing asymmetric sulfoxidation catalyzed by prazole sulfide monooxygenase (AcPSMO). The costly redox cofactor NADPH utilized by AcPSMO was regenerated by formate dehydrogenase with CO2 as the coproduct, which can be removed easily. During the scale-up process, oxygen supply was found to be the main limiting factor during the early phase of the reaction, while the instability of AcPSMO and the lack of the cofactor NADPH hindered progress during the middle and late phases of the 0.6 L reaction. Finally, by adjusting oxygen mass transfer and increasing the dissolved oxygen, the enzymatic reaction was stepwise amplified to a 120 L scale using a 300 L thermostatic stirred reactor, affording 95.9% conversion and 99.9% enantiomeric excess after 12 h. Extraction and refinement of the product resulted in 0.39 kg of the isolated esomeprazole (sodium salt), with 57.8% overall yield (73.4% before the salt-forming reaction) and 99.1% purity. Thus, a green-by-design system was constructed for the efficient and precise oxidation of omeprazole sulfide into esomeprazole with molecular O-2 as the green cosubstrate and CO2 and H2O as byproducts.