普拉格雷中间体的合成研究

Synthesis of the intermediate of prasugrel

目的探索制备普拉格雷合成重要中间体2-氟-α-环丙酰苄基溴的较优工艺条件。方法以邻氟溴苄为原料,经格氏反应和环丙基腈作用生成环丙基-2-氟苄基酮,再经α位溴化得到2-氟-α-环丙酰苄基溴。结果最佳配比为镁∶邻氟溴苄∶环丙基腈=1.1∶1∶0.8(摩尔比),洗脱液为石油醚∶乙酸乙酯=20∶1和15∶1(体积比),α-位溴化时用氢溴酸和过氧化氢代替液溴。结论改进后的合成方法工艺合理、可行,为工业化生产提供了实验依据。

Objective To synthesize the α-cyclopropylcarbonyl-2-fluorobenzyl bromide, which is an important intermediate for the synthesis of prasugrel, the optimum reaction conditions were explored by experiments. Methods Cyclopropyl 2-fluorobenzyl ketone was prepared starting from 2-fluorobenzyl bromide through Grignard reaction with eyelopropaneearbonitrile. Then α-cyclopropylcarbonyl-2-fluorobenzyl bromide was synthesized by the α-H of cyclopropyl 2-fluorobenzyl ketone being substituted by the atom of Br. Results The optimized matching conditions were Mg： 2-fluorobenzyl bromide： cyclopropanecarbonitrile = 1.1 ： 1 ： 0. 8 and the eluent was ligroin： acetic ether = 20：1 and 15： 1. The bromine,which was used for the substitution of α-H by the atom of Br was replaced by hydrobromic acid and hydrogen peroxide. Conclusions The upgraded process was rational and feasible, which could be used as experimental basis for mass production.