恩曲他滨的合成工艺优化  

Synthetic Procedure Optimization of Emtricitabine

作　　者：李苏 顾继山 吴晓宇[1] 熊芸[1] 孙国锋[1] 丁一刚[1] 刘生鹏[1] LI Su;GU Jishan;WU Xiaoyu;XIONG Yun;SUN Guofeng;DING Yigang;LIU Shengpeng(School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430205,China)

机构地区：[1]武汉工程大学化工与制药学院,湖北武汉430205

出　　处：《武汉工程大学学报》2020年第2期129-133,共5页Journal of Wuhan Institute of Technology

基　　金：湖北省技术创新专项重大项目(2017ACA086)。

摘　　要：为满足临床对HIV药物的需求,优化了HIV核苷类逆转录酶抑制剂恩曲他滨的合成工艺。以苯甲酸钠和溴乙醛缩二乙醇为原料,经五步反应,即缩合、缩醛水解、脂肪酶Novozyme 435催化环化和酰化,合成中间体(2R,5S)-2-苯甲酰氧甲基-5-乙酰氧基-1,3-氧硫杂环戊烷,然后将其进行偶联、水解反应得到99.7%纯度的恩曲他滨,总收率为51.3%。制备的化合物通过核磁共振氢谱(1H NMR)以及核磁共振碳谱(13C NMR)确证。与已有工艺相比,本合成工艺具有安全性好、收率高、成本低的特点,易于生产出符合原料药质量标准的产品。To meet the requirements of clinical drugs of human immunodeficiency virus(HIV),the synthetic procedure of the HIV nucleoside analogue reverse transcriptase inhibitor emtricitabine was optimized.The key intermediate(2R,5S)-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane was synthesized from sodium benzoate and bromoacetaldehyde diethyl acetal as starting materials via five-step reactions including condensation,hydrolysis,cyclization and acylation by immobilized Candida antarctica lipase B(Novozyme 435).Then the intermediate was subjected to coupling and hydrolysis to get the target compound emtricitabine with 51.3%total yield and up to 99.7%purity.The chemical structures of compounds were confirmed by nuclear magnetic resonance spectroscopy(1H NMR and 13C NMR).Compared with the preceding process,the improved process has the characteristics of safety,higher yield and lower cost,which can meet the quality standards of active pharmaceutical ingredient.

关 键 词：恩曲他滨 脂肪酶Novozyme 435 (2R 5S)-2-苯甲酰氧甲基-5-乙酰氧基-1 3-氧硫杂环戊烷 合成 

分 类 号：R978.7[医药卫生—药品]