帕比司他合成工艺研究

Study on the synthetic process of panobinostat

目的改进帕比司他的合成工艺。方法以对苯二甲醛为起始原料,经还原、Knoevenagel-Doebner缩合、酯化、氯代反应合成关键中间体(E)-3-[4-(氯甲基)苯基]丙烯酸甲酯;以苯肼和5-氯-2-戊酮为原料制备中间体2-甲基色胺;两个中间体经亲核取代、氨解反应合成帕比司他。结果与结论目标物帕比司他的结构经MS和1H-NMR谱确证,纯度为99.51%(HPLC面积归一化法),总收率为32.5%。该路线操作简便,适合工业化生产。

A practical and feasible method for the preparation of panobinostat was described in this paper.The key intermediate methyl(E)-3-[(4-chloromethyl)phenyl]acrylate was synthesized from terephthalaldehyde via a four-step process with a total yield of 58.9%.Another intermediate 2-methyltryptophan was synthesized from phenylhydrazine and 5-chloro-2-pentanone through a Fischer indole synthesis with a yield of 75.4%.Panobinostat was synthesized from the two intermediates via nucleophilic substitution and ammonolysis reaction with an overall yield of 32.5%and a purity(HPLC)of 99.51%.The novel process is easy to operate and suitable for large-scale preparation.