替韦立马两种立体异构杂质的合成及鉴定

摘要

目的 合成替韦立马原料药中的两种立体异构杂质(1,2),用于其质量及毒理学研究.方法 通过改变环庆二烯与顺丁酸酐的缩合条件,合成了托烷酸酐异构体,然后与对三氟甲基苯甲酰肼反应形成替韦立马立体异构体.结果与结论 两种杂质经核磁氢谱、质谱确证为4,4a,5,5a,6,6a-六氢-4,6-亚乙烯基-1H环丙[f]异苯并呋喃-1,3(3aH)-二酮及3aR,4S,4aS,5aR,6R,6aS-3,3a,4,4a,5,5a,6,6a-六氢-4,6-亚乙烯基-1H环丙[f]异苯并呋喃-1,3(3aH)-二酮.反应温度和反应时间对不同构象托烷酸酐中间体的含量影响较大,反应温度提高及反应时间延长均增加了托烷酸酐中间体含量,最终增加目标产品的杂质量.所得两种杂质为替韦立马原料药质量及毒理学研究奠定了基础.%Objective To synthesize two impurities (1 and 2) from tecovirimat for further study of their quality and toxicology.Methods By changing the condensation condition of cycloheptatriene and maleic anhydride,two tropan intermediates were obtained.Further condensations of these intermediates with 4-(trifluoromethyl) benzoic acid hydrazide yielded tecovirimat isomers.Results and Conclusion The structure of two tecovirmat isomers was verified by 1 H NMR and MS.The high condensation temperature of cycloheptatriene and maleic anhydride and long reaction time increased the content of tropane anhydride intermediate,resulting in the increase in tecovirimat isomers.The synthetic tecovirimat isomers can be used as reference substances of impurities in quality and toxicological studies.