PARP抑制剂veliparib的合成工艺改进  

Improved synthesis of PARP antagonist veliparib

作　　者：吕天翔[1,2] 王凌霄[2] 王晓奎[2] 胡春[1] 周辛波[2] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国药物化学杂志》2013年第6期476-479,共4页Chinese Journal of Medicinal Chemistry

基　　金：国家"重大新药创制"科技重大专项(2010ZX09401-405-03)

摘　　要：目的设计合成PARP抑制剂veliparib,并对其合成工艺进行优化。方法以(R)-吡咯烷-2-羧酸为起始原料,经过环合、甲基化、开环、N-H保护、水解、酸氨缩合、咪唑合环、脱保护和成盐酸盐等步骤不对称合成目标化合物veliparib。结果设计的合成路线与文献不同,目标化合物veliparib的合成总收率为9.48%,目标化合物和中间体的结构经1H-NMR和GC-MS确证。结论设计了全新的合成路线,该路线具有原料易得、价格低廉、操作简便、安全等优点,避免了使用手性柱分离目标化合物,适合于工业化生产。Veliparib（ ABT-888 ）, a novel oral PARP inhibitor has entered the clinical study for the treatment of metastatic melanoma, colon cancer, glioblastoma multiforme and breast cancer. A novel improved synthet- ic method for veliparib with （R）-pyrrolidin-2-carboxylic acid as the chiral starting material via 9 steps reac- tions, including condensation, methylation, esterification, N-H protection, hydrolysis, amidation, cyclization, hydrogenation and salt-forming, was described in this paper. The structures of the target compound and the key intermediates were confirmed with melting points, optical rotation, mass spectra and proton NMR. The total yield is 9. 48%. Compared with the reported literature, any chiral column for separation of the target compound or intermediates is not used,therefore,the synthetic process for veliparib is of easily available raw materials, low cost, simple operation, safety, and suitable for industrialized production.

关 键 词：PARP抑制剂 veliparib 合成工艺 不对称合成 

分 类 号：TQ464[化学工程—制药化工]