达克替尼的合成工艺研究

Study on synthetic process to dacomitinib

目的优化达克替尼的合成工艺。方法以2-氨基-4-氟苯甲酸为起始原料,经缩合成环、硝化、卤代、亲核取代、苯环上亲核取代、还原、亲核取代、芬克尔斯坦卤素交换及亲核取代等10步反应制得目标化合物达克替尼。结果目标化合物结构经ESI-MS、^(1)H-NMR、^(13)C-NMR谱确证,总收率为39.2%(以2-氨基-4-氟苯甲酸计),纯度达99.5%(HPLC法)。结论该工艺原料易得、产品纯度高、操作简单、适合工业化生产。

Dacomitinib(1) was an anti-tumor drug, which had a great market prospect in the coming years.A practical and feasible method for the preparation of 1 was described in this paper.Dacomitinib was synthesized from 2-amino-4-fluorobenzoic acid(2) by 10-step synthetic process with an overall yield of 39.2%(based on compound 2-amino-4-fluorobenzoic acid) and purity of 99.5%.The intermediates and target compound were characterized by MS,^(1)H-NMR and ^(13)C-NMR.The synthetic method had the advantages of easy availability of raw materials, simple operation and high product purity, and was suitable for industrial production.