富马酸比索洛尔合成中的杂质分析及控制  

Impurity Analysis and Control in the Synthesis of Bisoprolol Fumarate

作　　者：陈慧[1] 樊琳静[2] 李丽娟[1] 高生彬 姚军[2] 

机构地区：[1]河北化工医药职业技术学院制药工程系,石家庄050026 [2]河北科技大学化学与制药工程学院,石家庄050018 [3]石药集团中诺药业(石家庄)有限公司,石家庄050041

出　　处：《科学技术与工程》2013年第32期9755-9758,共4页Science Technology and Engineering

基　　金：河北省科技支撑计划项目(09276410D);河北化工医药职业技术学院重点立项课题;河北省教育厅资助项目(Z2012192)资助

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%。In the synthesis of bisoprolol fumarate, a high content impurity was found, and it was never been re- corded. The generation of the impurity was analyzed by HPLC, and its structure was identified by 1 H-NMR, 13 C- NMR 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 con- tent 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%.

关 键 词：比索洛尔 富马酸 杂质 控制 

分 类 号：TQ460.6[化学工程—制药化工]