作　　者： (刘佳明）; (杨丰宇）; (赵俐翔）; (申迪）; (许佑君）;

机构地区： 沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处： 《中国药物化学杂志》 2017年第4期297-302,共6页

摘　　要： 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。 In order to optimize the synthetic route to flibanserin,a reliable HPLC analytical method was established involving the intermediates,product and main related impurities of the route. The product was synthesized via cyclization,deprotection and two nucleophilic substitutions from 1,2-diaminobenzene and ethyl acetoacetate. In this route,commercially available and easy-to-purify ethyl acetoacetate was employed instead of the benzoylacetate as the starting material,which could avoid the detection of acetophenone generated from the subsequent deprotection step during the quality control study. Also,1,2-dibromoethane was used as the two-carbon-unit building block,and the formed bromide could be easily converted to the final product.Seven related substances of this route were synthesized and purified as the authentic samples for the quality control study. Thus,flibanserin could be synthesized in 4 steps in 47. 0% yield with more than 99. 5% purity,and any related impurity was minimized to less than 0. 1% by HPLC analysis. This concise,lab-scaled process could be useful for further industrial manufacturing.

关 键 词： 氟班色林 有关物质 监测 合成工艺