阿地溴铵的合成工艺改进

Improved synthesis of aclidinium bromide

目的改进阿地溴铵的合成方法。方法以草酸二甲酯为原料,经格氏反应、酯交换反应和亲核取代反应制备阿地溴铵。结果与结论目标化合物结构经MS、~1H-NMR谱确证,总收率为33.1%(以草酸二甲酯计)。改进后的工艺具有操作简便、收率高、成本低的特点,适合工业化生产。

Aclidinium bromide, a novel long-acting inhaled anticholinergic bronchodilator, is developed by Almirall and Forest Laboratories for the treatment of chronic obstructive pulmonary disease. An improved synthetic process was developed in this paper. Aclidiniurn bromide was prepared from （3R）-1-azabicyclo [ 2.2.2 ] oct-3-yl hydroxy （ di-2-thienyl ） acetate （ 5 ） and 3-bromopropoxy benzene （ 8 ）. The intermediate 5 was synthesized from dimethyl oxalate via Grignard reaction and transesterification. The intermediate 8 was obtained from phenol and 1,3-dibromopropane via nucleophilic reaction. The overall yield of aclidinium bro- mide was 33.1% （based on dimethyl oxalate）. The structure of the target compound was confirmed by MS and ^1H-NMR.