卡利拉嗪关键中间体1-(2,3-二氯苯基)哌嗪盐酸盐的合成

Synthesis of Cariprazine Key Intermediate 1-(2,3-dichlorophenyl)Piperazine Hydrochloride

以便宜易得的间氯苯胺为原料,经特戊酰基保护,以四氢呋喃做溶剂在双二甲胺基乙基醚存在下用丁基锂和1,1,2-三氟三氯乙烷在两个官能团之间引入一个氯原子,再经盐酸和醋酸回流脱保护,最后与双(2-氯乙基)胺盐酸盐以1,3-二甲基-2-咪唑啉酮做溶剂在醋酸钠存在下发生关环反应得到卡利拉嗪关键中间体1-(2,3-二氯苯基)哌嗪盐酸盐。该新方法原料便宜易得,总成本较低,无高危反应,适合工业化放大生产。

Cariprazine key intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride was synthesized successively through pivaloyl chloride protection from commercial available starting material 3-chloroaniline,introducing a chlorine atom between two group using carbon anion with n-BuLi and 1,1,2-trichlorotrifluoroethane in presence of bis(2-dimethylaminoethyl)ether in THF,de-protection in hydrochloric acid and acetic acid,subsequently substitution with bis(2-chloroethyl)amine hydrochloride in presence of sodium acetate in 1,3-dimethyl-2-imidazolidinone.This new method had many benefits such as materials cheap and commercial available,lower cost,exclusive of high risk reaction and suitable for industrial scale-up production.