Alpelisib的合成工艺改进

Improved Synthetic Process of Alpelisib

文章对小分子抗肿瘤药物alpelisib(BYL719,1)的合成方法进行了改进。以2,4-二溴吡啶为原料,依次经亲核取代、硅醚化保护和脱保护、甲磺酰化及取代等5步反应引入三氟甲基得到关键中间体4-溴-2-(1,1,1-三氟-2-甲基丙烷-2-基)-吡啶(8)。中间体8与[2-[(叔丁氧羰基)氨基]-4-甲基噻唑-5-基]硼酸在钯催化下,经Suzuki偶联反应得[4-甲基-5-[2-(1,1,1-三氟-2-甲基丙烷-2-基)吡啶-4-基]噻唑-2-基]氨基甲酸叔丁酯,再进行脱Boc保护及缩合等反应得到目标化合物1,总收率约15.9%。

In this study,the synthetic method of the small molecule antineoplastics alpelisib(BYL719,1)was improved.Using 2,4-dibromopyridine as the starting material,the key intermediate 4-bromo-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine(8)was obtained via 5 steps,including nucleophilic substitution,silylation protection,deprotection,methanesulfonylation and substitution.Intermediate 8 condensed with[2-[(tert-butoxycarbonyl)amino]-4-methylthiazol-5-yl]boronic acid under the Pd-catalyzed Suzuki coupling reaction to give[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-tert-butyl thiazol-2-yl]carbamate.Followed by removing the Boc protection group and condensation,the target compound 1 was obtained in a 15.9%total yield.