枸橼酸托法替尼的合成工艺改进
Optimized synthesis process of tofacitinib citrate
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摘要: 为了提高收率和简化操作工艺，在文献方法的基础上，对JAK3抑制剂枸橼酸托法替尼的合成工艺进行了改进。以2，4-二氯-7H-吡咯并［2，3-d］嘧啶和（3R，4R）-1-苄基-N，4-二甲基哌啶-3-胺二盐酸盐为起始原料，经亲核取代、催化转移氢化、氰乙酰化、成枸橼酸盐等4步反应制得枸橼酸托法替尼，晶型与原研药一致。工艺优化后，收率优于文献报道的合成工艺收率，反应条件温和，适合工业化生产。Abstract: In order to improve the yield and simplify the operation, the synthesizing process of JAK3 inhibitor tofacitinib citrate was improved based on the analysis of the methods previously published.Using 2, 4-dichloro-7H-pyrrolo [2, 3-d] pyrimidine and (3R, 4R)-1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride as starting materials, tofacitinib citrate was obtained through four steps of nucleophilic substitution, catalytic transfer hydrogenation, cyanide acetylation and citrate salt, and its crystal form was consistent with the original research.After optimization, the yield was better than those reported in literature, and the mild reaction conditions were suitable for industrial production.
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Keywords:
- tofacitinib citrate /
- JAK3 inhibitor /
- synthesis /
- optimization
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