阿地溴铵原料药有关物质的合成

Synthesis of related substances of aclidinium bromide

目的研究阿地溴铵原料药中有关物质来源及合成方法,为产品质量控制提供依据和杂质对照品。方法通过对阿地溴铵原料药制备过程可能产生的杂质推测,以(R)-(-)-3-奎宁醇和3-苯氧基溴丙烷为原料合成杂质A;以R-2,2-二(2-噻吩基)-2-羟基乙酸奎宁-3-基酯和1,3-二溴丙烷为原料,控制不同反应条件合成杂质B和杂质C。结果与结论合成的3种杂质经~1H-NMR、HRMS谱确证,HPLC测定纯度在98%以上,可作为阿地溴铵原料药的杂质对照品,其中杂质B和杂质C为首次报道;建立了专属性好、灵敏度高的阿地溴铵杂质分析方法,为阿地溴铵原料药的质量控制提供帮助。

In order to control the quality of aclidinium bromide, three impurities were synthesized. Impurity A was synthesized from （R）-（ - ）-3-quinuclidinol and 3-phenoxypropyl bromide. Impurity B and impurity C were obtained from quaternary ammonium salt formation between （R）-quinuclidin-3-yl-2-hydroxy-2,2-di （thiophen-2-yl） acetate and 1,3-dibromopropane in different conditions. The structures of impurities A, B, C were confirmed by 1H-NMR and HR-MS ,and the purities were over 98% via HPLC ,which can be used as reference substances for the aclidinium bromide. A HPLC method, which showed high specificity and sensibility of detecting the three impurities and two raw materials, has been built.