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  

High yield process study of key intermediate of novelβ-lactamase inhibitors in continuous flow microreactors

作　　者：张丹华 赵晨熙 董江湖 王池 邓鑫浩 严琼姣 ZHANG Danhua;ZHAO Chenxi;DONG Jianghu;WANG Chi;DENG Xinhao;YAN Qiongjiao(Pharmaceutical Research Institute,Wuhan Institute of Technology,Wuhan 430205,China)

机构地区：[1]武汉工程大学药物研究院,武汉430205

出　　处：《华中师范大学学报（自然科学版）》2024年第6期661-667,共7页Journal of Central China Normal University：Natural Sciences

基　　金：湖北省重点研发计划项目(2023BCB055).

摘　　要：连续流微型反应器是近年来兴起的新型反应器,具有温和、高效、安全的特点.为解决细菌耐药性问题,优化新型β-内酰胺酶抑制剂制备工艺,该文以N-叔丁氧羰基-L-焦谷氨酸苄酯(2)为原料,在微通道反应器中通过硫叶立德增碳反应合成了β-内酰胺酶抑制剂关键中间体(S)-5-氧代-2-叔丁氧羰基氨基-6-二甲基亚砜基-5-己烯酸苄酯(1),经氢谱、碳谱及高分辨质谱鉴定,产物与目标物一致.考察了不同碱、温度、流速、当量比对反应的影响,结果显示在恒定室温条件下以DMSO为溶剂、t-BuONa为碱、n(化合物2):n(TMSOI):n(t-BuONa)=1.0∶1.2∶1.2、两氟化乙烯-丙烯盘管内径均为0.8 mm、泵A、B、C流速均为50μL·min^(-1)、总保留时间为26.67 min时,目标产物的收率可达95%.优化后的工艺条件,显著加快反应速率的同时提高了反应收率,使得该技术能更好地应用于工业生产中.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 newβ-lactamase inhibitors.The key intermediate ofβ-lactamase inhibitors(S)-5-oxo-2-tert-butoxycarbonylamino-6-dimethylsulfoxide-5-hexenoate benzyl ester(1)was synthesized from N-ter t-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,13 C 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,t-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 50μL·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.

关 键 词：Β-内酰胺酶抑制剂 连续流 微反应器 

分 类 号：R914.5[医药卫生—药物化学]