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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。
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