依非韦伦关键中间体的合成

Synthesis of the Key Intermediate of Efavirenz

报道了依非韦伦关键中间体(S)-1-(2-氨基-5-氯苯基)-1-三氟甲基-3-环丙基-2-丙炔-1-醇(1)的合成。对氯苯胺(2)与特戊酰氯反应得N-(4-氯苯基)-2,2-二甲基丙酰胺(4),4与三氟乙酸酐在三氯化铝作用下经傅-克酰基化反应后,酸性水解得4-氯-2-三氟乙酰基苯胺盐酸盐(5),革除了危险试剂正丁基锂的使用。化合物5经碱化得4-氯-2-三氟乙酰基苯胺(6)。化合物6在氯化锌和(1R,2S)-1-苯基-2-(1-吡咯烷基)-1-丙醇(7)形成的催化体系中与少量纯品1和环丙乙炔氯化镁经不对称自催化反应制得1。该步反应用氯化锌代替价昂且危险的二乙基锌;收率由79%提高至85.6%;配体7可被有效回收,回收率98%,降低了成本。优化后的工艺反应条件温和,各步反应收率优良,总收率69.5%(以2计)。

The key intermediate of efavirenz： （S） -1- （2-amino-5-chlorophenyl） - 1-trifluoromethyl-3-cyclopropyl- 2-propyne-l-ol （1） was prepared, p-Chloroaniline （2） reacted with pivaloyl chloride to give N-（4-chlorophenyl）-2,2- dimethylpropanamide （4）. After a Friedel-Crafts acylation of compound 4 catalyzed by aluminum trichloride, and a hydrolysis under acidic conditions, 4-chloro-2-（trifluoroacetyl）aniline hydrochloride （5） was obtained. In this step, the hazardous reagent n-butyllithium was abolished. Compound 5 was basified to afford 4-chloro-2-（trifluoroacetyl）aniline （6）. Then compound 6 reacted with chloromagnesium cyclopropylacetylide under the catalytic system formed by zinc chloride and （1R,2S）-1-phenyl-2-（1-pyrrolidinyl）-1-propanol （7） and a small amount of purified 1 to obtain the target compound 1 by asymmetric autocatalysis with an overall yield of 69.5 % （based on 2）. In the last step, zinc chloride was used instead of diethylzinc, the yield was increased from 79% to 85.6%. And ligand 7 was recovered with a recovery rate of 98 %, which could reduce the cost successfully. This improved synthetic route has mild reaction conditions and the yield of each step was excellent.