琥珀酸美托洛尔有关物质的结构分析

The Structure Analysis of the Related Substances of Metoprolol Succinate

为了对琥珀酸美托洛尔产品中的杂质进行定量控制,对美国和英国药典中涉及的13种有关物质进行了溯源分析,开发设计合成路线并完成了对其中4种有关物质的合成,通过核磁共振和质谱确定了其化学结构.在美托洛尔的制备中,发现了1种从未被报道的、含量较高的杂质(命名为Dimer),并对该杂质进行了分离富集,通过核磁共振和质谱确定了其化学结构.根据该杂质的结构分析了其产生的原因,在此基础上,通过改变实验条件,成功地将琥珀酸美托洛尔中该杂质的含量控制在0.1%以下.

To perform the quality control of metoprolol succinate,the generations of the impurities reported by USP and EP were analyzed.The synthetic routes of four impurities were designed.Impurities were prepared successfully and their structures were comfirmed by1HNMR and MS.During the scale-up manufacturing,an unreported new impurity（named Dimer） was found,and it was isolated from the final product.The chemical structure of the Dimer was elucidated,and the source of its generation was analyzed.With these results of the experiments,the reaction condition was optimized,and the content of the impurity was controlled successfully below 0.1 % in the final product.