奥拉帕尼的合成工艺改进

Improved Synthesis of Olaparib

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.