托法替尼的结构鉴定与构象分析

Structure Determination and Conformational Analysis of Tofacitinib

关键词:  托法替尼  构象  核磁共振  关键中间体  受阻旋转

Key words:  Tofacitinib  conformation  nuclear magnetic resonance  key intermediate  restricted rotation

摘要:

目的 鉴定合成的托法替尼的化学结构，并对其构象进行分析。方法 用DMSO-d6作溶剂，通过测试该合成样品的¹H-NMR、¹H-NMR（DMSO-d6+D₂O）、¹³C-NMR（包括常温、高温60℃、高温120℃的图谱）、¹H-¹H COSY、DEPT、HSQC、HMBC图谱及其关键中间体的常温¹³C-NMR图谱，参照文献与专著，鉴定合成的托法替尼的化学结构，并分析其构象。结果 确证了合成的托法替尼的化学结构。其常温¹³C-NMR图谱中，大多数信号出现裂分，升温到120℃，裂分信号合并，推导在常温下，因为围绕酰胺键的旋转受阻，托法替尼在DMSO-d6溶液中以2种构象存在。结论 合成的托法替尼结构正确，且常温下在DMSO-d6溶液中以2种构象存在。

Abstract:

OBJECTIVE To investigate the structure and conformation of synthesized Tofacitinib. METHODS The ¹H-NMR,¹H-NMR(DMSO-d6+D₂O),¹³C-NMR(at room and elevated temperature of 60 and 120℃), ¹H-¹H COSY, DEPT, HSQC, HMBC spectra of Tofacitinib and ¹³C-NMR of its key intermediate at room temperature were recorded in DMSO-d6. Based on the related literature, monograph and the ¹³C-NMR comparison of Tofacitinib and its key intermediate, the structure and conformation analysis of synthesized Tofacitinib in DMSO-d6 were carried out. RESULTS The structure of synthesized Tofacitinib was determined on the basis of these spectral data. Most of the signals of Tofacitinib in ¹³C-NMR spectrum at room temperature were split while these split signals were merged when the temperature was increased to 120℃. It maight have two conformations in DMSO-d6 at room temperature due to the restricted rotation about the carbon-nitrogen bond of the amide group. CONCLUSION The structure of synthesized Tofacitinib is confirmed and it may have two conformations in DMSO-d6 at room temperature.