铜催化合成艾拉莫德中间体杂质
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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.
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.
引文
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[2]MUCKE H.Iguratimod:a new disease-modifying antirheumatic drug[J].Drugs Today,2012,48(9):577-586.
[3]INABA T,TANAKA K,TAKENO R,et al.Synthesis and anti-inflammatory activity of 7-methanesulfonyl-amino-6-phenoxychromones.antiarthritic effect of the 3-formylamino compound(T-614)in chronic inflammatory disease models[J].Chem.Pharm.Bull.,2000,48(1):131-139.
[4]汪燕翔,高红,曹凤华,等.艾拉莫德的合成研究[J].中国新药杂志,2006,15(23):162-164.
[5]丁磊,李小敏,殷晓进,等.艾拉莫德(T-614)的合成工艺研究[J].江苏药学与临床研究,2006,14(3):162-164.
[6]韩冰冰.一种艾拉莫德中间体的制备方法:107 021 891[P].2017-08-08.
[7]王一男,胡虹.新药艾拉莫德的合成放大实验[J].上海化工,2007,32(12):22-24.
[8]KHAN T,FORNEFELD T,HUBNER D,et al.Palladiumcatalyzed 4-fold domino reaction for the synthesis of a polymeric double switch[J].Org.Lett.,2018,20(7):2 007-2 010.
[9]王晔峰,曾京辉,崔晓瑞.铜催化C-N交叉偶联反应的研究进展[J].有机化学,2010,30(2):181-199.
[10]成宜娟,孙丽萍.铜催化C-N,C-O偶联反应的研究进展[J].有机化学,2013,33(5):877-890.
[11]ZHANG Y,HSUNG R P,TRACEY M R,et al.Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides.synthesis of heteroaromatic amine substituted ynamides[J].Org.Lett.,2004,6(7):1 151-1 154.