艾拉莫德的合成工艺改进  

Improvement of synthesis process of iguratimod

作　　者：王栋 陆俊 钟健 龙玺国 徐琳寓 王崇益 马玉恒 马文静 WANG Dong;LU Jun;ZHONG Jian;LONG Xiguo;XU Linyu;WANG Chongyi;MA Yuheng;MA Wenjing(College of Material and Chemical Engineering,Chuzhou University,Chuzhou 239000;Production Technology Department,Jiangsu Runan Pharmaceutical CO.,LTD.Huai’an 223001,China)

机构地区：[1]滁州学院材料与化学工程学院,安徽滁州239000 [2]江苏润安制药有限公司生产技术部,江苏淮安223001

出　　处：《广东药科大学学报》2021年第1期51-54,共4页Journal of Guangdong Pharmaceutical University

基　　金：滁州学院校启动基金(2020qd09,2018qd06);滁州学院国家级大学生创新创业训练计划项目(2020CXXL119,202010377027)。

摘　　要：目的改进艾拉莫德合成中的胺基甲酰化反应工艺。方法通过活性酯法,甲酸(2)与N,N‐羰基二咪唑(CDI)反应得到中间态甲酰基咪唑(3),再与起始原料2‐氨基‐1‐(2‐甲氧基‐4‐甲磺酰胺基‐5‐苯氧基苯基)乙酮盐酸盐(4)缩合得到甲酰胺基甲基‐2‐甲氧基‐4‐甲磺酰胺基‐5‐苯氧基苯基酮(5),收率由67.3%提高至91.7%;(5)经过甲氧基水解得到甲酰胺基甲基‐2‐羟基‐4‐甲磺酰胺基‐5‐苯氧基苯基酮(6);(6)经过环合反应得到艾拉莫德(1)。结果与结论目标产物结构经1H‐NMR、13C‐NMR和MS确证,氨基甲酰化、甲氧基水解和环合3步反应总收率为68.1%。改进后的甲酰化工艺反应进程快,条件温和,反应选择性高,具有较高的商业化价值。Objective:The synthetic process of aminoformylation in the synthesis of iguratimod was improved.Methods Intermediate formyl imidazole(3)was synthesized by the reaction of formic acid(2)with N,N'‐carbonyldiimidazole(CDI),N‐(2‐(2‐methoxy‐4‐(methylsulfonamido)‐5‐phenoxyphen‐yl)‐2‐oxoethyl)formamide(5)was synthesized by the reaction of N‐(4‐(2‐aminoacetyl)‐5‐methoxy‐2‐phenoxyphenyl)methanesulfonamide hydrochloride(4)and(3),and the yield increased from 67.3%to 91.7%.N‐(2‐(2‐hydroxy‐4‐(methylsulfonamido)‐5‐phenoxyphenyl)‐2‐oxoethyl)formamide(6)was obtained by methoxy hydrolysis reaction of(5),and iguratimod(1)was synthesized from(6)by cyclization.Results and Conclusion The structure of the target product has been verified by 1H‐NMR/13C‐NMR and MS and the total yield of carbamoylation,methoxy hydrolysis and cyclization was 68.1%.The improved formylation process has the advantages of fast reaction process,mild reaction condition and less side reaction and high commercial value.

关 键 词：艾拉莫德 环氧化酶‐2抑制剂 N N'‐羰基二咪唑 合成 

分 类 号：R914.5[医药卫生—药物化学]