论文部分内容阅读
目的对氟班色林的合成工艺进行系统研究,建立简便HPLC方法以对各步中间体和终产品进行质量控制。方法以邻苯二胺和乙酰乙酸乙酯为起始原料,通过环合、脱保护、两次亲核取代完成氟班色林的合成。建立了该药合成所涉及的各步中间体、产物及主要有关物质的HPLC检测方法,并以此法监测合成工艺过程。结果与结论本文选用易购买和纯化的乙酰乙酸乙酯(而非苯甲酰乙酸乙酯)为原料,避免了后续脱保护产生苯乙酮的检测,简化了质量控制方法。同时,选用1,2-二溴乙烷来引入两碳单位,生成的溴代物更易于胺化。针对选定的合成路线,分析可能的有关物质共计7种,并进行了定向合成、结构确证,确立了涵盖中间体、终产品和主要有关物质的HPLC检测方法,以满足初步质量研究的要求。四步反应的总收率可达47.0%(以邻苯二胺计),终产品的纯度达到99.5%以上,单个有关物质均控制在0.1%以下。优化后的合成工艺操作简单、适合工业化生产。
OBJECTIVE To systematically study the synthesis of Flibanserin and to establish a simple and convenient HPLC method for the quality control of each intermediate and final product. Methods o-Phenylenediamine and ethyl acetoacetate as starting materials, through cyclization, deprotection, two nucleophilic substitution Flibanserin synthesis. The HPLC method for the determination of intermediates, products and major related substances involved in the synthesis of this drug was established and the synthetic process was monitored by this method. Results and Conclusion In this study, ethyl acetoacetate (instead of ethyl benzoylacetate) was purchased and purified as a starting material to avoid the subsequent detection of acetophenone by deprotection and to simplify the quality control method. At the same time, the use of 1,2-dibromoethane to introduce two carbon units, the resulting bromide is more easily aminated. According to the selected synthetic routes, a total of seven possible related substances were analyzed, and directional synthesis and structural confirmation were carried out. HPLC detection methods covering intermediates, final products and major related substances were established to meet the requirements of preliminary quality studies. The total yield of the four-step reaction can reach 47.0% (with o-phenylenediamine), the purity of the final product reaches more than 99.5% and the single related substances are controlled below 0.1%. The optimized synthesis process is simple and suitable for industrial production.