β-内酰胺酶抑制剂关键中间体的微通道技术合成  

Synthesis of key intermediates ofβ-lactamase inhibitors by microchannel technology

作　　者：赵晨熙 王池 董江湖 张丹华 邓鑫浩 陈尧 严琼姣 ZHAO Chenxi;WANG Chi;DONG Jianghu;ZHANG Danhua;DENG Xinhao;CHEN Yao;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：《武汉工程大学学报》2024年第1期7-10,17,共5页Journal of Wuhan Institute of Technology

基　　金：湖北省重点研发计划项目(2023BCB055)。

摘　　要：为了优化二氮杂双环辛烷(DBO)类新型β-内酰胺酶抑制剂的关键中间体(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-羧酸(Ⅰ)的合成工艺,采用微通道技术,通过对反应溶剂、温度、停留时间和碱的优化,以加快反应速率,提高反应产率。结果表明:采用连续流微通道技术,以(2S,5R)-6-苄氧基-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-羧酸苄酯(Ⅱ)为原料,在氢氧化锂的丙酮水溶液中,温度45℃,反应时间20 min,水解制备得到DBO类新型β-内酰胺酶抑制剂的关键中间体(Ⅰ),经氢谱、碳谱、高分辨质谱鉴定,产物与目标化合物一致,目标产物的收率可达95%。该微通道合成方法显著加快反应速率的同时提高了反应收率,对DBO类新型β-内酰胺酶抑制剂的工业化生产具有应用前景。Microchannel technology was used to improve the synthesis efficiency of(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid(Ⅰ),a key intermediate of novelβ-lactamase inhibitors based on diazabicyclooctane(DBO).Through the investigation of solvent,temperature,residence time and base,the process conditions were optimized.The results show that the hydrolysis of(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester(II)in microchannel reactor is best conducted with acetone as a solvent and lithium hydroxide as a base at 45℃for 20 min.The product was identified by 1 H nuclear magnetic resonance spectroscopy,13C nuclear magnetic resonance spectroscopy and high resolution mass spectroscopy.The key intermediate(Ⅰ)is obtained in 95%yield.Thus this technology significantly increases the rate and yield of this reaction and makes it feasible to industrial production.

关 键 词：DBO类化合物 Β-内酰胺酶抑制剂 连续流微通道技术 水解 

分 类 号：R914.5[医药卫生—药物化学]