Tofacitinib的合成

Synthesis of Tofacitinib

4-氯-7H-吡咯并[2,3-d]嘧啶(2)经保护、取代、脱保护得到N-[(3R,4R)-1-苄基-4-甲基哌啶-3-基]-N-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(7),7脱苄基后无需分离,直接与氰乙酸乙酯缩合得到抗类风湿性关节炎药tofacitinib,总收率约57%(以2计),纯度99.4%。

Tofacitinib, an anti-rheumatoid arthritis drug, was synthesized from N-[ （3R,4R）-l-benzyl-4- methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine（7） by removing the benzyl group and condensing with ethyl cyanoacetate in one-pot synthesis. The intermediate 7 could be obtained from 4-chloro-7H-pyrrolo E2,3- d]pyrimidine （2） by protection, substitution and deprotection. The total yield of tofacitinib was about 57 % （based on compound 2） with purity of 99.4 %.