4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮合成工艺研究

Synthesis of 4-(4-fluoro-3-(piperazine-1-carbonyl) benzyl)phthalazin-1(2H)-one

对PARP抑制剂4-[4-氟-3-(哌嗪-1-羰基)苄基]-2H-酞嗪-1-酮的合成工艺进行了改进,使用更为价廉的邻苯二甲酰亚胺作为起始原料,经选择性还原、加成、水解制得关键中间体2-氟-5-[(4-氧代-3,4-二氢酞嗪-1-基)甲基]苯甲酸,然后与1-叔丁氧羰基哌嗪缩合制得目标化合物,总收率达41.9%。用质谱、核磁共振氢谱确定了目标化合物的结构。与原工艺相比,该方法起始原料价廉易得,降低了成本,避免了大量的含碱废水,更易于工业化。

The synthesis of the PARP inhibitors 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2 H)-one was optimized. The key intermediate was prepared with phthalimide as the starting material. Through reduction,addition reaction and hydrolysis,2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl) methyl]benzoic acid was obtained.The target compound was synthesized by the condensation of tert-butyl piperazine-1-carboxylate with the key intermediate mentioned above. The total yield was 41. 9%. The structures of the target product and key intermediates were verified by MS and1 H NMR. Compared with the original process,the starting material of this optimal synthetic procedure was cheap,reducing the cost and avoiding a large amount of alkali-containing waste water. And it was easier to industrialize.