替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物的简便合成

Facile Synthesis of Key Intermediates of Tinib Drugs,N-Arylquinazolin-4-amines

目的 研究替尼类药物的关键中间体N-芳基喹唑啉-4-胺化合物的新合成方法,优化反应条件,确定反应底物适用性,推测反应可能机理。方法 以取代邻氨基苯甲腈(1a~1e)和芳胺(2a~2e)为原料,甲酸为反应底物和溶剂,Cu(OTf)_(2)为催化剂,发生多组分串联反应一锅合成N-芳基喹唑啉-4-胺化合物(3a~3g),考察催化剂及用量、溶剂、反应物用量、反应温度和反应时间对反应的影响。结果 在Cu(OTf)_(2)的催化下,取代邻氨基苯甲腈、芳胺和甲酸能顺利发生串联的加成/缩合/环化反应,在取代邻氨基苯甲腈5 mmol,芳胺6 mmol,Cu(OTf)_(2) 0.5 mmol,甲酸20 mL,110℃反应12 h的条件下,以80%~95%的收率得到7个N-芳基喹唑啉-4-胺化合物,目标产物结构经~1H-NMR和^(13)C-NMR确证。结论 该方法为合成替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物提供了一种高效简便的绿色工艺,反应条件温和,产物收率高,操作安全简便,对环境友好。

OBJECTIVE To establish a new synthesis method of N-arylquinazolin-4-amines,the key intermediates of tinib drugs,optimize the reaction conditions,determine the applicability of reaction substrates,and speculate the possible reaction mechanism.METHODS N-Arylquinazolin-4-amines(3 a-3 g) were synthesized via Cu(OTf)_(2)-catalyzed one-pot multicomponent tandem reactions of substituted 2-aminobenzonitriles(1 a-1 e),arylamines(2 a-2 e) and formic acid.The effects of catalyst and its dosage,the solvent,the amount of reactants,the reaction temperature,and the reaction time on the multicomponent tandem reaction were investigated.RESULTS The tandem addition/condensation/cyclization reactions of substituted 2-aminobenzonitriles,arylamines and formic acid catalyzed by Cu(OTf)_(2) were achieved successfully to give seven N-arylquinazolin-4-amines with yields of 80%-95% under the conditions of substituted 2-aminobenzonitrile 5 mmol,arylamines 6 mmol,formic acid 20 mL,Cu(OTf)_(2) 0.5 mmol,reaction temperature 110 ℃,reaction time 12 h.The structures of the target compounds were confirmed by ~1H-NMR and ^(13)C-NMR.CONCLUSION The method is a green process for the efficient and facile synthesis of N-arylquinazolin-4-amines,the key intermediates of tinib drugs,which is mild in reaction condition,high in yield,simple and safe in operation,and friendly to environment.