高光学纯度的氯吡格雷合成工艺研究  

Synthesis of High Optical Purity Clopidogrel

作　　者：潘岩 谢其亮 陈重 陈琼 杨俊杰 PAN Yan;XIE Qi-liang;CHEN Zhong;CHEN Qiong;YANG Jun-jie(Col lege of Biological and Pharmaceutical Engineering, Xinyang Agriculture and Forestry University, Xinyang 464000, China;Henan Lingrui Pharmaceutical Co., Ltd., Xinyang 464000, China)

机构地区：[1]信阳农林学院生物与制药工程学院,河南信阳464000 [2]河南羚锐制药股份有限公司,河南信阳464000

出　　处：《化学试剂》2018年第7期703-706,共4页Chemical Reagents

基　　金：河南省科技攻关项目(172102210121)

摘　　要：以（R）-（-）-邻氯扁桃酸为原料合成中间体（R）-2-（4-硝基苯磺酰氧基）-2-（2-氯苯基）乙酸甲酯,以2-噻吩乙胺为原料合成中间体4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐,以上两种中间体缩合得氯吡格雷,产物光学纯度（e.e.%）〉99%。通过正交试验设计方法考察反应温度、反应溶剂和投料比对氯吡格雷e.e.%的影响。结果表明,温度对反应的影响最大,优化后工艺条件：反应温度为25℃,丙酮为溶剂,投料比为1.3∶1。在该条件下,缩合产率为91.6%,氯吡格雷的e.e.%〉99%,有效解决了氯吡格雷光学纯度问题,且工艺简单易行、重现性好、适合工业化生产。Methyl（ R）-（-）-2-（ 4-nitrobenzenesulfonyloxy）-2-（ 2-chlorophenyl） acetate was synthesized using（ R）-（-）-2-chloromandelic acid as the raw material and 4,5,6,7-tetrahydrotieno [3,2-c] pyridinium chloride was synthesized using thiophene-2-ethylamine as the raw material. Clopidogrel was obtained via condensation of this two intermediates,the optical purity is greater than 99%.Orthogonal test was used to investigate the effect of reaction time,reaction temperature and the ratio of both compound on the e. e.% of clopidogrel.The result showed that the reaction temperature had the most significant effect and the optimum reaction condition as follows： reaction temperature for 25 ℃,solvent for acetone and the ratio of both compound for 1. 3 ∶1.The yield of condensation process was 91. 6%,and the e. e.% of clopidogrel more than 99%.The optimal purity problem of clopidogrel was effectively resolved,and the preparation process of clopidogrel was easy and reliable,it can be applied on industrial production.

关 键 词：氯吡格雷 光学纯度 合成 

分 类 号：R914.2[医药卫生—药物化学]