Abstract

An efficient protocol is developed for the synthesis of Rilpivirine intermediate 4-[(4-chloro-2-pyrimidinyl) amino]benzonitrile hydrochloride via a simple two-step approach. Initially 1-(4-cyanophenyl)guanidine hydrochloride was prepared by reacting 4-cyanoaniline hydrochloride with aqueous cyanamide in diglyme. Then ethyl acetate was reacted with methyl formate in presence of anhydrous sodium methoxide to generate ethyl 3-oxopropanoate in situ, which was further reacted with 1-(4-cyanophenyl)guanidine hydrochloride to generate the pyrimidine intermediate. Chlorination of the pyrimidine intermediate afforded the target compound, Rilpivirine. The significant advantages of the method include cost-effectiveness, excellent yield and scope for large-scale production.

摘要

为通过简单的两步法合成 Rilpivirine 中间体 4-[(4-chloro-2-pyrimidinyl) 氨基] 苯甲腈盐酸盐开发了一种有效的方案。最初，1-(4-氰基苯基)胍盐酸盐是通过4-氰基苯胺盐酸盐与氨基氰水溶液在二甘醇二甲醚中反应制备的。然后乙酸乙酯与甲酸甲酯在无水甲醇钠存在下原位生成3-氧代丙酸乙酯，再与1-(4-氰基苯基)胍盐酸盐反应生成嘧啶中间体。嘧啶中间体氯化得到目标化合物利匹韦林。该方法的显着优势包括成本效益、出色的产量和大规模生产的范围。