铜催化合成艾拉莫德中间体杂质  

Synthesis of Iguratimod Intermediate Impurity via Copper Catalysis

作　　者：刘巧云[1] 王宏义 秦海芳[1] 杨怡[1] 高雨琼 陈剑 赵金亮 LIU Qiao-yun;WANG Hong-yi;QIN Hai-fang;YANG Yi;GAO Yu-qiong;CHEN Jian;ZHAO Jin-liang(Institute of Pharmaceutical and Environmental Engineering,Changzhou Vocational Institute of Engineering,Changzhou 213164,China;Changzhou Jiade Pharmaceutical Technology Co.,Ltd., Changzhou 213164,China)

机构地区：[1]常州工程职业技术学院制药与环境工程学院,江苏常州213164 [2]常州佳德医药科技有限公司,江苏常州213164

出　　处：《化学试剂》2019年第2期203-206,共4页Chemical Reagents

基　　金：江苏高校品牌专业建设工程资助项目(PPZY-2015B178)

摘　　要：3-甲磺酰胺基-4-苯氧基苯甲醚是合成抗风湿新药艾拉莫德的关键中间体,但在制备过程中生成了一种双取代产物的工艺杂质,且分离困难。开发一种高效制备艾拉莫德中间体的工艺杂质——3-(N,N-二甲磺酰基)胺基-4-苯氧基苯甲醚的新方法,即由5-甲氧基-2-苯氧基苯胺经桑德迈尔反应碘代、再经铜催化反应制得。考察了铜催化反应的催化剂、缚酸剂、反应温度、溶剂对反应的影响。结果表明:Cu(OAc)2·H2O/1,10-菲罗啉为催化剂和配体、碳酸钾为缚酸剂、二甲基亚砜(DMSO)为溶剂,100℃反应8 h,能够以良好的反应收率得到产物。其结构经1HNMR、13CNMR、DEPT和质谱确证。该方法具有步骤简单、收率高等特点,为艾拉莫德及中间体的杂质研究和质量控制提供了帮助。3-Methylsulfonamido-4-phenoxyanisole is a key intermediate for synthesizing the anti-rheumatic new drug Iguratimod.However,a process-related impurity of disubstituted product of which formed during the preparation process and was difficult for separation.A novel effective procedure for preparing the Iguratimod intermediate impurity,3-( N,N-dimethylsulfonyl) amido-4-phenoxyanisole was developed.It was prepared by Iodination of 5-methoxy-2-phenoxyaniline via Sandmeyer reaction,and then by copper-catalyzed reaction.The influences of catalyst,deacid reagent,temperature and solvent of the copper-catalyzed reaction were investigated.The results indicated that the procedure proceeds smoothly to give the corresponding products in good yield by using Cu( OAc)2·H2 O/1,10-phenanthroline as catalyst/ligand,with K2 CO3 as acid binding agent and DMSO as solvent for 8 h at100 ℃.The structure was confirmed by1 HNMR,13 CNMR,DEPT and MS. This reaction method has advantages of simple procedure and high yield,and is helpful for impurity research and quality control of Iguratimod and its intermediates.

关 键 词：铜催化 艾拉莫德中间体 杂质研究 合成 

分 类 号：R971[医药卫生—药品]