富马酸贝达喹啉有关物质的合成

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。

Synthesis of related substance of bedaquiline fumarate

Bedaquiline fumarate is a drug for multi-drug-resistant tuberculosis w hich w as deve-loped by Janssen Pharmaceutica. An unspecified impurity w as found in the synthesis of bedaquiline fumarate. In order to confirm the unspecified impurity,debromination of bedaquiline w as synthesized through tw o steps,using 3-benzyl-6-bromo-2-methoxyquinoline as the starting material,and confirmed by M S,1H-NM R and13C-NM R.It＇s confirmed that unspecified impurity is the debromination of bedaquiline through HPLC. The quality of bedaquiline fumarate meet the pharmacopoeia standard w hich all impurities content w ere below 0. 1%.