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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。