溴丙胺太林杂质A的合成  

Synthesis of the impurity A of propantheline bromide

作　　者：李波[1] 张文轩[1] 王冬梅[1] 吴松[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所活性物质的发现与适药化研究北京市重点实验室,北京100050

出　　处：《中国药物化学杂志》2014年第6期459-463,共5页Chinese Journal of Medicinal Chemistry

基　　金：国家"十二五"重大新药创制科技重大专项(2012ZX09301002-001)

摘　　要：目的为加强对溴丙胺太林原料药的质量控制,合成溴丙胺太林杂质A以作为对照品使用。方法以呫吨酸(3)为起始原料,采用两条合成路线合成关键中间体9-羟基丙胺太林:1)首先氧化引入羟基,然后再经过甲酯化和酯交换反应得到9-羟基丙胺太林;2)首先进行酯化反应,再经过氧化反应引入羟基得到9-羟基丙胺太林。最后经过季铵盐化反应得到终产物。结果与结论相比第一条合成路线,第二条路线更简短,收率更高。目标化合物结构经1H-NM R、13C-NM R和M S确证,HPLC检测纯度达到98%以上,合成的杂质可以作为溴丙胺太林原料药质量控制的杂质对照品。In order to better perform the quality control of propantheline bromide,the content determination of impurtiy A（ 9-hydroxypropantheline bromide） w as required according to the standard comparison method in the United States Phamacopeia（ USP）. Therefore,the impurity A w as intended to prepare in this paper.Tw o routes w ere designed to synthesize the crucial intermediate 9-hydroxypropantheline using xanthanoic acid as starting material. In the first route,the 9-hydroxypropantheline w as obtained by oxidation to introduce hydroxyl group on the starting material,follow ed by methyl esterification and interesterification reaction in poor total yield of 4. 8%. In contrast,the second route w as successfully implemented to give the crucial intermediate in moderate total yield of 51. 9% by changing the order of the oxidation and esterification reactions. Lastly,impurity A w as synthesized by quaternization of 9-hydroxypropantheline. The structure w as confirmed by1H-NM R,13C-NM R and M S.

关 键 词：溴丙胺太林 杂质A 合成 氧化 酯化 

分 类 号：R914[医药卫生—药物化学]