【摘要】 在富马酸比索洛尔的制备中,发现了1种从未被报道的、含量较高的杂质,通过1H-NMR、13C-NMR、MS和HPLC对其进行了溯源分析和结构确证,并定向合成了该杂质。根据其产生根源,优化醚化反应工艺条件,结果表明,当n(对异丙氧基乙氧基甲基苯酚)∶n(环氧氯丙烷)=1∶1.2,以蒸馏水为溶剂,NaOH为催化剂,反应温度70℃,反应时间4 h时,该杂质的含量得到了有效控制;并通过精制使最终产品富马酸比索洛尔中的该杂质去除掉,其他杂质含量不超过0.1%。更多还原

【Abstract】 In the synthesis of bisoprolol fumarate,a high content impurity was found,and it was never been recorded. The generation of the impurity was analyzed by HPLC,and its structure was identified by 1H-NMR、13CNMR and MS. The impurity was rational synthesized. The reaction conditions of etherification were optimized. The results showed that molar ratio of 4-[( 2-isoproxy ethoxy)-methyl]-phenol to epichlorohydrin was 1∶ 1. 2,reaction temperature 70 ℃,using distilled water as the solvent,NaOH as the catalyst,reaction time 4 h,the impurity content were effectively controlled. The impurity of the final product was removed after refining,and the contents of the other impurities were controlled below 0. 1%.更多还原