新型 β-内酰胺酶抑制剂关键中间体在连续流 微反应器中的高收率工艺研究.

张丹华; 赵晨熙; 董江湖; 王池; 邓鑫浩; 严琼姣

The continuous flow microreactor is a novel reactor that has gained prominence in recent years due to its notable features of gentleness, exceptional efficiency, and safety. This study aimed to address the issue of bacterial drug resistance and improve the production process of new β-lactamase inhibitors. The key intermediate of β-lactamase inhibitors (S)-5-oxo-2-tert-butoxycarbonylamino-6-dimethylsulfoxide-5- hexenoate benzyl ester (1) was synthesized from N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester (2) by sulfur ylide carburization reaction in a microchannel reactor, and the product was consistent with the target by ¹H NMR. 13C NMR, and HRMS. In this paper, the effects of base. temperature, flow rate, and equivalent ratio on the reaction were investigated. The results indicated that a yield of up to 95% for the target product could be achieved under the following conditions: using DMSO as the solvent. -BuONa as the base and maintaining an equivalent ratio of 1.0 1.2 1.2 between compound 2. TMSOI, and t-BuONa. Additionally, the fluoride-propylene coils had an inner diameter of 0.8 mm, while pumps A. B. and C operated at a flow rate of 50 µL. min-1. Furthermore, the total retention time was 26.67 minutes at a constant room temperature. The process conditions were optimized, the reaction rate was significantly accelerated and the reaction yield was increased at the same time for better application in industrial production.

MICROREACTORS; CHEMICAL yield; DRUG resistance in bacteria; RF values (Chromatography); MANUFACTURING processes

Journal of Central China Normal University, 2024, Vol 58, Issue 6, p661

1000-1190

Academic Journal

10.19603/j.cnki.1000-1190.2024.06.006