枸橼酸托法替布有关物质的合成
Synthesis of the related substances of tofacitinib citrate
高超 1崔阳 1许敏 1潘瑞雪 1程合丽 1江玉娟1
作者信息
- 1. 山东明仁福瑞达制药股份有限公司山东省骨科疼痛类工程技术研究中心,山东济南 250104
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摘要
目的 合成枸橼酸托法替布制备工艺中产生的5种有关物质,为其质量研究提供对照品.方法 以N-甲基-N-[(3R,4R)-4.甲基哌啶-3-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(7)为原料,与甲醛经甲基化反应得到有关物质A;以化合物7为原料,与不同的羧基底物经酰胺缩合反应得到有关物质B和C;以化合物7为原料,经过氧化、还原反应得到有关物质D;以托法替布(9)为原料,经过氧化反应得到有关物质E.结果 与结论有关物质A～E的结构均经1H-NMR、ESI-MS谱确证,其纯度均大于95％(HPLC法),可用于枸橼酸托法替布的质量研究.
Abstract
Five related substances of tofacitinib citrate were synthesized to provide references for the quality control of tofacitinib.Using N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(7)as the starting material,methylation with formaldehyde formed related substance A.Using compound 7 as the starting material,the condensations of the carboxyl group with different amide substrates gave related substances B and C.Using compound 7 as the starting material,the oxidation and reduction reaction formed related substance D.Using tofacitinib(9)as the starting material,the oxidation reaction formed related substance E.The structures of five impurities were confirmed by 1H-NMR and ESI-MS,and the purities of all impurities were higher than 95％(HPLC),which could be used for the quality study of tofacitinib citrate.
关键词
枸橼酸托法替布/有关物质/结构确证/合成Key words
tofacitinib citrate/related substance/structure confirmation/synthesis引用本文复制引用
出版年
2024
NETL
NSTL
万方数据