文章摘要
刘长春,顾言语,梁 恩.微波促进下N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺的合成[J].精细化工,2019,36(4):
微波促进下N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺的合成
Synthesis of N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine under Microwave Irradiation
投稿时间:2018-08-20  修订日期:2018-12-11
DOI:
中文关键词: N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺  Afatinib  Dacomitinib  微波辐射  中间体
英文关键词: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine  afatinib  dacomitinib  microwave irradiation  intermediate
基金项目:
作者单位E-mail
刘长春 江苏食品药品职业技术学院 ccl67@126.com 
顾言语 江苏食品药品职业技术学院  
梁 恩 江苏食品药品职业技术学院  
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中文摘要:
      以2-溴-4-氟-5-硝基苯甲腈为起始原料,在CuI和微波促进下,与3-氯-4-氟苯胺加成后,再与甲酰胺发生串联的胺化和缩合环化反应合成抗癌药Afatinib(阿法替尼)和Dacomitinib(达克替尼)的关键中间体N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺,对反应条件进行了优化。结果表明:在CuI(摩尔分数20%)和微波促进下,n(2-溴-4-氟-5-硝基苯甲腈):n(3-氯-4-氟苯胺)=1:1,回流反应20 min,制备得到2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒,收率93.8%;然后,在CuI/4-羟基-L-脯氨酸(摩尔分数10%)和微波促进下,n(2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒):n(甲酰胺)=1:2,80℃反应10 min,以96.4%的收率得到目标产物。
英文摘要:
      N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine, the key intermediate of the anticancer drug Afatinib and Dacomitinib, was synthesized via the addition of 2-bromo-4-fluoro-5-nitrobenzonitrile with 3-chloro-4-fluoroaniline, following cascade amination and condensation-cyclization with formamide catalyzed by cuprous iodide under microwave irradiation. The optimal reaction conditions were investigated. The reaction results showed that 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzimidamide in 93.8% yield was synthesized when 20% cuprous iodide (mole fraction) was used as catalyst, molar ratio of 3-methoxyaniline and 3,3-dimethoxypropionate was 1:1, refluxed for 20 min under microwave irradiation. Subsequently, the target product, N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine was obtained with a yield of 84.5% in the presence of 10% cuprous iodide/4-hydroxyl-L-proline (mole fraction), and with n(2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzimidamide):n(formamide) of 1:2 at 80℃ for 10 min under microwave irradiation.
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