帕瑞昔布钠有关物质的合成

Synthesis of the related substances of parecoxib sodium

目的为了提高对帕瑞昔布钠原料药及其关键中间体的质量控制,本文合成了帕瑞昔布钠的3个有关物质A~C。方法以2-(邻溴苯基)乙酸为起始原料,经氯代、傅克酰化、成肟、环合、脱水、磺酰化及氨化反应得到有关物质A;以2-(乙酰基)溴苯为原料,经偶联、成肟、环合及脱水、磺酰化及氨化反应得到有关物质B;以2-(间溴苯基)乙酸为原料,经氯代、傅克酰化、成肟、环合、脱水、磺酰化及氨化反应得到有关物质C。结果与结论合成的3个有关物质的结构均经^(1)H-NMR、^(13)C-NMR、HRMS谱确证,化学纯度大于98%,可满足帕瑞昔布钠的分析方法开发要求,为帕瑞昔布钠的杂质研究和质量控制提供科学依据。

In order to improve the quality control of parecoxib sodium and its key intermediates, three related substances A-C were synthesized.Impurity A is obtained through chlorination, Friedel-Crafts acylation, oxime formation, cyclization, dehydration, sulfonylation and amination reactions from 2-(2-bromophenyl)acetic acid.Similarly, impurity B through coupling, oxime formation, cyclization, dehydration, sulfonylation and amination reactions from 1-(2-bromophenyl)ethanone and impurity C through chlorination, Friedel-Crafts acylation, oxime formation, cyclization, dehydration, sulfonylation and amination reactions from 2-(3-bromophenyl)acetic acid.The structures of the three related substances′ were confirmed by ^(1)H-NMR,^(13)C-NMR,and HR-MS.Their chemical purities are more than 98%,which can meet the requirements of analytical method development of parecoxib sodium and provide scientific basis for the impurity research and quality control of parecoxib sodium.