米拉贝隆和去羟基米拉贝隆的合成
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摘要
以对硝基苯乙胺和(R)-环氧苯乙烷经开环、还原,与2-(2-氨基噻唑-4-基)乙酸直接缩合三步合成制备了治疗膀胱过度活动症原料药米拉贝隆,并以苯乙酰氯和对硝基苯乙胺为原料,经酰化、还原、缩合制得主要杂质去羟基米拉贝隆。所得目标化合物经红外、核磁共振氢谱、核磁共振碳谱和高分辨质谱等结构确证。改进后的米拉贝隆制备工艺反应条件温和、步骤短、操作简便,适合工业放大生产。
Over active bladder drug mirabegron was synthesized in three steps from( R)- phenyloxirane and 4-nitrophenethylamine by ring opening- substitution,reduction,and condensation with 2-( 2- aminothiazol- 4- yl) acetic acid. The main impurity,dehydroxymirabegron was also synthesized from phenylacetyl chloride and 4- nitrophenethylamine by acylation,reduction,and condensation. The structures of mirabegron and dehydroxymirabegron were confirmed by IR,1HNMR,13 CNMR and HRMS. The improved process has mild reaction conditions,short steps and simple operation,which is very suitable for amplification of production.
Over active bladder drug mirabegron was synthesized in three steps from( R)- phenyloxirane and 4-nitrophenethylamine by ring opening- substitution,reduction,and condensation with 2-( 2- aminothiazol- 4- yl) acetic acid. The main impurity,dehydroxymirabegron was also synthesized from phenylacetyl chloride and 4- nitrophenethylamine by acylation,reduction,and condensation. The structures of mirabegron and dehydroxymirabegron were confirmed by IR,1HNMR,13 CNMR and HRMS. The improved process has mild reaction conditions,short steps and simple operation,which is very suitable for amplification of production.
引文
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[6]胡凡,王伸勇,贾新赞,等.一种米拉贝隆的合成方法:中国,103193730[P].2013-04-17.
[7]章磊,谭支敏,焦慧荣,等.米拉贝隆有关物质的合成[J].中国医药工业杂志,2014,45(1):9-12.
[2]唐启东,宫平.米拉贝隆[J].中国药物化学杂志,2012,22(6):544.
[3]范鸣.膀胱过度活动症治疗药Mirabegron[J].药学进展,2012,36(3):133-135.
[4]Tatsuya M,Takayuki S,Kenichi O,et al.Antidiabetic,antilipemic,and hypoglycemic agents;adrenergic stimulants:US,6346532[P].2002-02-12.
[5]Kawazoe S,Sakamoto K,Awamura Y,et al.Alpha-form or beta-form crystal of acetanilide derivative:EP,1440969[P].2002-10-29.
[6]胡凡,王伸勇,贾新赞,等.一种米拉贝隆的合成方法:中国,103193730[P].2013-04-17.
[7]章磊,谭支敏,焦慧荣,等.米拉贝隆有关物质的合成[J].中国医药工业杂志,2014,45(1):9-12.