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第 36 卷第 4 期 精 细 化 工 Vol.36, No.4
201 9 年 4 月 FINE CHEMICALS Apr. 2019

精细化工中间体
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

刘长春，顾言语，梁 恩

（江苏食品药品职业技术学院 药学院，江苏 淮安 223003）

摘要：以 2-溴-4-氟-5-硝基苯甲腈为原料， CuI 为催化剂，在微波促进下与 3-氯-4-氟苯胺进行加成反应后，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，并对反应条件进行了优化。结果表明：在 CuI 用量为 20%(以 2-溴-4-
氟-5-硝基苯甲腈的物质的量为基准，下同)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%；在 CuI 与 4-羟基-L-脯氨酸
用量均为 10%〔以 2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒的物质的量为基准，下同〕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
N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺。
关键词：N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺；阿法替尼；达克替尼；微波辐射；精细化工中间体
中图分类号：O626.32；TQ253.23 文献标识码：A 文章编号：1003-5214 (2019) 04-0776-05

Synthesis of N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-
4-amine under Microwave Irradiation

LIU Chang-chun, GU Yan-yu, LIANG En
（School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huai'an 223003, Jiangsu, China）

Abstract: N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine, a key intermediate for the
synthesis of anti-cancer drugs, such as Afatinib and Dacomitinib, was synthesized by an addition of
2-bromo-4-fluoro-5-nitrobenzonitrile with 3-chloro-4-fluoroaniline, followed by cascade amination and
condensation-cyclization with formamide in the presence of a catalytic amount of cuprous iodide under
microwave irradiation. The reaction conditions were optimized. The results showed that 2-bromo-N-(3-
chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzimidamide in 93.8% yield was synthesized when the dosage of
cuprous iodide was 20% (based on the molar amount of 2-bromo-4-fluoro-5-nitrobenzonitrile, the same
below), the molar ratio of 2-bromo-4-fluoro-5-nitrobenzonitrile to 3-chloro-4-fluoroaniline was 1 : 1, and
the mixture was refluxed for 20 min under microwave irradiation. Subsequently, the target product was
obtained with a yield of 96.4% under the conditions of cuprous iodide dosage 10% (based on the molar
amount of 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzimidamide, the same below), 4-
hydroxyl-L-proline dosage 10%, molar ratio of 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-
nitrobenzimidamide to formamide 1 : 2, reaction temperature 80 ℃, microwave irradiation time 10 min.
Key words: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine; Afatinib; Dacomitinib; microwave
irradiation; fine chemical intermediates

Afatinib（阿法替尼），化学名称 N-{4-[(3-氯-4- 6-基}-4-(二甲基氨基)-2-丁烯酰胺；Dacomitinib（达
氟苯基)氨基]-7-{[(3S)-四氢呋喃-3-基]氧基}喹唑啉- 克替尼），化学名称 N-{4-[(3-氯-4-氟苯基)氨基]-7-

收稿日期：2018-08-20; 定用日期：2018-12-19; DOI: 10.13550/j.jxhg.20180609
作者简介：刘长春（1967—），男，教授，E-mail：ccl67@126.com。