ABT-263中间体羧酸片段合成研究

Synthesis of ABT-263 Intermediate Carboxylic Acid

报道了Bcl-2家族蛋白抑制剂ABT-263(1)中间体羧酸片段即4-(4-((2-(4-氯苯基)-5,5-二甲基环己基-1-烯)甲基)哌嗪-1-基)苯甲酸(2)的合成方法。首先4,4-二甲基环己酮与三溴化磷和N,N-二甲基甲酰胺反应生成第一个中间体化合物2-溴-5,5-二甲基环己基-1-烯甲醛(3),经Suzuki偶联反应,还原、卤代、胺化,最后经水解、酸化得到目标产物(2)。经过6步反应,使用廉价易得的原料和试剂,反应条件温和,后处理方便,纯化方法简单,总产率达到48.0%,明显高于现有文献报道产率,适合大规模生产。各步反应产物结构经过1H NMR确认。

As the key intermediate of an oral Bcl-2 family protein inhibitor ABT-263 （ 1 ）, the synthetic method for 4- （ 4- （ （ 2- （4-chlorophenyl） -5,5-di-methylcyclohex-1 -enyl） methyl） piperazin-1 -yl ） benzoic acid （ 2 ） was reported. It was the reaction of 4,4-dimethylcyclohexanone with phosphorus tribromide and N,N-dimethylformamide to form the first intermediate 2-bromo-5,5-dimethyl-cyclohex-1-ene carbaldehyde （3） ; and then after the reactions of Suzuki coupling, reduction, halogenation, amidation, hydrolysis and acidification to afford （2）. It was prepared in 47% total yield by six steps, significantly higher than the reported yield. The synthesis with simple and mild conditions, convenient workup procedure is suitable for large scale production. The structures of all products were confirmed by 1H NMR.