替韦立马两种立体异构杂质的合成及鉴定  

Synthesis of two impurities from poxvirus inhibitor tecovirimat

作　　者：周尚民[1,2] 李海涛[2] 董铭心[2] 王孝花[2] 戴秋云[2] 

机构地区：[1]湘潭大学化学学院,湖南湘潭411105 [2]军事医学科学院生物工程研究所,北京100071

出　　处：《军事医学》2013年第6期446-449,共4页Military Medical Sciences

基　　金：国家新药创制重大专项资助项目(2009ZX09301-002)

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。方法通过改变环庚三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 1H 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.

关 键 词：替韦立马 抗痘病毒药物 杂质 合成 

分 类 号：R927[医药卫生—药学]