PARP抑制剂奥拉帕利的合成及晶型A的制备

Synthesis of the PARP Inhibitor Olaparib and Prepration of Its Crystal Form A

制备PARP抑制剂奥拉帕利晶型A.以2-氟-5-[(4-氧代-3,4-二氢酞嗪-1-基)甲基]苯甲酸为原料,与N-叔丁氧羰基哌嗪缩合为酰胺,脱去叔丁氧羰基保护,再与环丙基甲酸缩合,经三步反应制得奥拉帕利粗品.粗品经乙醇水溶液处理获得晶型A.目标产物的化学结构被1H-NMR,^(13)C-NMR,MS和元素分析确证,晶型经XRPD,DSC,TGA表征,总收率为51%.优化后的合成路线反应条件温和,操作简便,对环境友好,适宜工业化生产.

The paper is to prepare crystal form A of PARP inhibitor Olaparib.The crude Olaparib was prepared from 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid by amidation with N-tert-butyloxycarbonylpiperazine,removing the protected N-boc group,and then condensation with cyclopropyl acid.Finally,the crude was treated with aqueous ethanol to produce crystal form A,which overall yield was 51%.The chemical structure of the target molecule was confirmed by 1H-NMR,^(13)C-NMR,MS and elemental analysis,and the crystal form was characterized by XRPD,DSC,TGA.In conclusion,the optimized synthetic route has the advantages of mild reaction conditions,operation easiness,environmental friendliness,and is suitable for industrial production.