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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 stereoisomeric impurities (1,2) for Tirofir’s APIs for their quality and toxicology studies. Methods The enantiomer of tropane anhydride was synthesized by changing the condensation conditions of cycloheptene and maleic anhydride, and then reacted with p-trifluoromethylbenzohydrazide to form the stereoisomers of tivaprol. RESULTS AND CONCLUSIONS The two impurities were confirmed by 1H NMR and MS spectra as 4,4a, 5,5a, 6,6a-hexahydro-4,6-ethenylene-1H cyclopropa [f] isobenzofuran- 3 (3aH) -dione and 3aR, 4S, 4aS, 5aR, 6R, 6aS-3,3a, 4,4a, 5,5a, 6,6a-hexahydro-4,6-ethenylene-1H cyclopropane [f] isobenzofuran-1,3 (3aH) -dione. The reaction temperature and reaction time have a great influence on the content of different conformation of tropane anhydride intermediates. The increase of reaction temperature and the prolongation of reaction time increase the content of tropane anhydride intermediates and finally increase the impurity amount of the target product. The two impurities obtained for the Veremai API quality and toxicology study laid the foundation.