托法替布有关物质Ⅰ的结构鉴定及合成

Structural Identification and Synthesis of Related Substances Ⅰ of Tofacitinib

在托法替布原料药的质量研究过程中,通过LC-MS分析发现一个新的杂质,推测其结构为双[(3R,4R)-4-甲基-3-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]哌啶-1-羰基甲基]胺,命名为有关物质Ⅰ。本研究以(3R,4R)-4-甲基-3-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]哌啶和亚胺基二乙酸为原料合成该化合物,所得产物经1HNMR、13C NMR和ESI-MS确证结构,且合成产物的HPLC保留时间与托法替布粗品中发现的杂质一致。

In the quality study of tofacitinib bulk drug,a new impurity was identified by LC-MS,and its structure was speculated to be bis[(3 R,4 R)-4-methyl-3-[methyl(7 H-pyrrole[2,3-d]pyrimidin-4-yl)amino]piperidin-1-carbonylmethyl]amine(named as related substanceⅠ).So,this compound was synthesized from(3 R,4 R)-4-methyl-3-[methyl(7 H-pyrrole[2,3-d]pyrimidin-4-yl)amino]piperidine and iminodiacetic acid.And its structure was confirmed by 1 H NMR,13 C NMR and ESI-MS.The results showed that retention time of the synthesized product in HPLC was consistent with that of the impurity found in crude product of tofacitinib.