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

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¹³C-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。

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

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(3a-3g) were synthesized via Cu(OTf)₂-catalyzed one-pot multicomponent tandem reactions of substituted 2-aminobenzonitriles(1a-1e), arylamines(2a-2e) 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 ¹³C-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.