阿塞那平中杂质的合成

Synthesis of the impurities from asenapine

目的:为加强对阿塞那平药物的质量控制,合成了阿塞那平的4个杂质,其中杂质C和杂质D的合成为首次报道。方法:以11-氯-2,3-二氢-2-甲基-1H-二苯并[2,3:6,7]氧杂并[4,5-c]吡咯-1-酮(6)为起始原料,经还原反应合成杂质A,对A继续还原得到杂质B,利用氧气氧化杂质B可以得到杂质C;同样以6为起始物,经过二氧化锰氧化得到杂质D。结果与结论:目标化合物结构经1H-NMR,MS确证,HPLC检测纯度也都达到98%以上,合成的4种杂质可以作为阿塞那平药物质量控制的杂质对照品。该合成方法路线短,反应条件温和,原料易得,操作简单。

Objective ： To synthesize four impurities of asenapine, in particular, the first reported synthesis of impurities C and D, for strengthening the quality control of asenapine. Methods： ll-Chloro-2,3-dihydro-2- methyl-I H-dibenz[2,3：6,7 ] oxepino[4,5-c ] pyrrol-1-one was used as starting material （6）. Impurity A was ob- tained by reduction of 6, and impurity B was prepared by further reduction of A. Subsequently, oxidation of impu- rity B under O2 afforded impurity C. Similarly, oxidation of 6 by manganese dioxide afforded impurity D. Results and Conclusion： The structures of the target compounds were confirmed by 1H-NMR and MS, and their purities were over 98% tested by HPLC. These four synthesized impurities can be used as the reference substances of the impurities in the quality control of asenapine. This synthetic route is short, the condition is modest, and the materi- als are easy to get.