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目的在抗结核药富马酸贝达喹啉的合成工艺中发现易生成脱溴杂质。为了对原料药的有关物质进行定量控制,本文分析了该杂质产生的原因,设计并合成了杂质对照品。方法以3-苄基-6-溴-2-甲氧基喹啉(3)为原料,经正丁基锂脱溴制得3-苄基-2-甲氧基喹啉(7),7与3-二甲氨基-1-(萘-5-基)丙酮(4)反应,制得脱溴杂质1-(2-甲氧基-3-喹啉基)-4-二甲氨基-2-(1-萘基)-1-苯基-2-丁醇(2),该杂质经HPLC定位确证为贝达喹啉粗品中的难除杂质。结果与结论目标化合物经MS、1H-NM R和13C-NM R确证结构,并通过优化工艺条件,减少了该杂质的生成,使产品质量符合药典标准。
OBJECTIVE To find that debromination is easy to generate during the synthetic process of anti-tuberculosis drug betaine fumarate. In order to quantitatively control the related substances of APIs, this paper analyzes the causes of the impurities and designs and synthesizes the reference substance of impurities. Methods 3-Benzyl-2-methoxyquinoline (7), 7 (3) were prepared by debromination of 3-benzyl- Is reacted with 3-dimethylamino-1- (naphthalen-5-yl) propanone (4) to obtain debromination impurity 1- (2-methoxy-3-quinolyl) - (1-naphthyl) -1-phenyl-2-butanol (2), which impurity was confirmed by HPLC to be a hard-to-remove impurity in the crude formquinoline. Results and Conclusion The target compounds were confirmed by MS, 1H-NM R and 13C-NM R, and by optimizing the process conditions, the formation of the impurities was reduced and the product quality was in accordance with Pharmacopoeia standards.