连续流微反应技术合成瑞来巴坦关键中间体  

Synthesis of Relebactam Key Intermediate by Continuous Flow Microreaction Technology

作　　者：王池 董江湖 赵晨熙 张丹华 邓鑫浩 严琼姣 WANG Chi;DONG Jianghu;ZHAO Chenxi;ZHANG Danhua;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,湖北武汉430205

出　　处：《化学与生物工程》2024年第9期53-56,共4页Chemistry & Bioengineering

摘　　要：在连续流微反应器中,以4-((2 S,5 R)-5-((苄氧基)氨基)哌啶-2-甲酰胺基)哌啶-1-甲酸叔丁酯(Ⅱ)为原料,与三光气、N,N-二异丙基乙胺和10%磷酸水溶液构建多组分体系,经脲化反应合成了瑞来巴坦关键中间4-((2 S,5 R)-6-(苄氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺基)哌啶-1-甲酸叔丁酯(Ⅰ),其结构经^(1)HNMR、^(13)CNMR确证,并对其合成工艺进行了优化。结果表明,在溶剂为二氯甲烷、碱为N,N-二异丙基乙胺、流速为60μL·min^(-1)、保留时间为14.7 min、反应器1温度为0℃、反应器2温度为25℃的最佳条件下,目标化合物Ⅰ的收率可达98%。We constructed a multicomponent reaction system of 4-((2 S,5 R)-5-((benzoxy)amino)piperidine-2-formamido)piperidine-1-tert-butyl formate(Ⅱ)with triphosgene,N,N-diisopropylethylamine,and 10%phosphoric acid aqueous solution in a continuous flow microreactor,and obtained Relebactam key intermediate 4-((2 S,5 R)-6-(benzoxy)-7-oxo-1,6-diazabicyclic[3.2.1]octane-2-formamido)piperidine-1-tert-butyl formate(Ⅰ)by urea reaction.Moreover,we confirmed the structure of the target compoundⅠby^(1)HNMR and^(13)CNMR,and optimized the synthesis process.The results show that the yield of target compoundⅠcan reach 98%under the optimal conditions as follows:dichloromethane is adopted as the solvent,N,N-diisopropylethylamine is adopted as the base,the flow rate is 60μL·min^(-1),the retention time of 14.7 min,the temperature of reactor 1 is 0℃,and the temperature of reactor 2 is 25℃.

关 键 词：瑞来巴坦 连续流 微反应 环脲 三光气 

分 类 号：TQ463[化学工程—制药化工]