替卡格雷关键中间体的合成及工艺优化  

Synthesis of the Key Intermediate of Ticagrelor and Its Preparation Process Optimization

作　　者：郑乐贵[1] 赵洋[2] 程城[3] 赵金浩[3] 夏敏[1] 

机构地区：[1]浙江理工大学理学院,杭州310018 [2]浙江工业大学药学院,杭州310011 [3]浙江大学农药与环境毒理研究所,杭州310029

出　　处：《浙江理工大学学报（自然科学版）》2016年第5期765-768,共4页Journal of Zhejiang Sci-Tech University(Natural Sciences)

摘　　要：对新型抗凝血药替卡格雷的关键中间体（（5S ,6S ）-5,6-二羟基-2-氧杂-3-氮杂双环[2. 2. 1]庚烷-3-羧酸 苄酯, TG -1）进行了合成新工艺研究.首先以稳定的环己酮肟（ TG -1）为起始原料,创新性地采用操作简便、节能降污 的连续式反应方法合成TG-3,三步总收率为87% ,比文献值高出33%.然后采用廉价的 KMnCO替换了文献报道 的 OsCl进行双键氧化,并对反应温度、投料比和反应时间进行正交试验,确定了 KMnCi氧化的最佳工艺条件.产 品结构经1H NMR 和 MS 确证.As a key intermediate of new anticoagulant Ticagrelor,(5S,6S)-benzyl-5,6-dihydroxy-2-oxa-3-azabicyclo[2.2.1]heptane-3-carboxylate(TG-4),was synthesized by a new technology.First of all,more stable Cyclohexanone oxime(TG-1)was used as starting material,and TG-3 was synthesized through the innovative,simple and energy-saving method of continuous reaction.The overall yield of three steps was 87%,33% higher than other reports.Then,cheap KMnO_4 was used to replace the OsO_4 reported in literatures for oxidation of double bond,and the orthogonal test was done for the reaction temperature,time and molar ratio.Thus,the optimum process was acquired for potassium permanganate oxidation.The structure of product is confirmed by ~1 HNMR and MS.

关 键 词：替卡格雷 环己酮肟 连续式反应 双键氧化 

分 类 号：R972.9[医药卫生—药品]