奥拉帕尼的合成工艺改进  

Improved Synthesis of Olaparib

作　　者：李贝贝[1,2] 邱飞[1,2] 王立强[1,2,3] 

机构地区：[1]华侨大学分子药物研究院,福建泉州362021 [2]华侨大学生物医学学院,福建泉州362021 [3]广州优米健医药科技有限公司,广东广州510050

出　　处：《华侨大学学报（自然科学版）》2017年第4期521-524,共4页Journal of Huaqiao University(Natural Science)

基　　金：福建省自然科学基金资助项目(2015J01342);华侨大学研究生科研创新能力培育计划项目(1400216004)

摘　　要：对奥拉帕尼的合成工艺进行改进,采用邻羧基苯甲醛与亚磷酸二甲酯反应得到磷叶立德,然后,与2-氟-5-甲酰基苯腈进行Wittig-Horner反应、水解和环合反应制得关键中间体化合物6.化合物6制成酰氯后与4-环丙基羰基哌嗪反应制得奥拉帕尼,产物结构经高分辨质谱,核磁共振氢谱和碳谱等确证.对磷叶立德的制备、Wittig-Horner反应和酰化反应等进行了工艺优化.结果表明:5步反应总收率为38.9%(以邻羧基苯甲醛计),比文献报道略高;改进后的工艺降低反应成本,缩短反应时间,简化操作.The synthesis process of olaparib was improved.Olaparib was synthesized including 2-carboxybenzaldehydereacting with dimethyl phosphonate to get phosphorus ylide,Wittig-Horner reaction with 2-fluoro-5-cyanobenzaldehyde,hydrolyzation,cyclization to get the key intermediate 6,chloroformylation and reaction with 4-cyclopropyl carbonyl piperazine.The structure was confirmed by HRMS,~1 H NMR,and ^（13） C NMR.The process was improved including the preparation of phosphorus ylide,Wittig-Horner reaction and acylation.The result showed that the yield of the 5steps was 38.9%（2-carboxybenzaldehyde as a benchmark）which is a little higher than the yield reported in literature;the improved process has lowered the cost,shortened the reaction time and simplified the operation.

关 键 词：磷叶立德 邻羧基苯甲醛 亚磷酸二甲酯 WITTIG-HORNER反应 酰化反应 

分 类 号：R914.5[医药卫生—药物化学]