依非韦伦中间体的不对称合成

Asymmetric Synthesis of Efavirenz Intermediates

为了优化依非韦伦手性中间体(S)-1-(2-氨基-5-氯苯基)-1-三氟甲基-3-环丙基-2-丙炔-1-醇的不对称合成工艺。以对氯苯胺为起始原料,经过氨基保护、酰化反应、氨基脱保护、碱化、不对称加成得到目标化合物。所得化合物结构均经核磁共振氢谱和碳谱确证。得到不对称加成反应最佳工艺条件:2-甲基四氢呋喃/甲苯为溶剂,4-氯-2-(三氟乙酰基)苯胺的浓度为0.45 mol/L,4-氯-2-(三氟乙酰基)苯胺、(1R,2S)-1-苯基-2-(吡咯烷基)-1-丙醇与ZnCl2的摩尔比为1.0∶1.2∶1.3,总收率达79.8%(以对氯苯胺计),对映体过量98.2%。优化后的工艺条件具有成本低、收率高,适合工业生产的特点。

To improve the asymmetric synthesis process of chiral intermediate(S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyne-1-ol of efavirenz,we prepared the target compound via amino protection,acylation reaction,deprotection,alkalinization and asymmetric addition reaction with p-chloroaniline as the raw material.The chemical structure of compounds was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy.The optimum process conditions of asymmetric addition reactions were determined using 2-MeTHF/toluene as solvent,at 0.45 mol/L of 4-chloro-2-(trifluoro acetyl),mole ratio of 4-chloro-2-(trifluoro acetyl)aniline(/1R,2S)-1-phenyl-2-(pyrrolidinyl)-1-propanol/Zinc chloride of 1.0∶1.2∶1.3.Under above conditions,the total yield reaches 79.8%(calculated by p-chloroaniline)and the enantiomeric excess is 98.2%.The improved process has the characteristics of lower cost,higher yield,which is suitable for industrial production.