吉非替尼的合成新工艺研究  

Study on the New Synthesis Process of Gefitinib

作　　者：徐永平[1] 张洋[2,3] 王宏亮 吴建一[1,2,3] 

机构地区：[1]常州大学石油化工学院,常州213164 [2]嘉兴学院生物与化学工程学院,嘉兴314001 [3]浙江省芳烃磺酸工程技术研究中心,嘉兴314001

出　　处：《化学通报》2014年第12期1236-1239,共4页Chemistry

基　　金：嘉兴市科技局项目(2012AY1074)资助

摘　　要：以6-羟基-7-甲氧基喹唑啉-4-酮(1)为起始原料,在离子液体催化下与N-(3-氯丙基)吗啉(2)醚化,然后经氯代再与3-氯-4-氟苯胺进行亲核取代反应,得到目标产物吉非替尼,三步反应总收率为68.7%。通过改变反应物配比、离子液体用量和反应温度,得到了关键中间体3的优化制备工艺条件:n(1)∶n(2)=1.0∶1.2;离子液体四氟硼酸1-甲基-4-丁基咪唑鎓用量为原料1的质量的5%;95℃下反应5h。在此条件下,醚化收率约93.6%。该路线具有反应条件温和、分离简单、路线短和总收率较高的特点,为吉非替尼的工业化生产提供了实验依据。A new approach to the synthesis of gefitinib was proposed,i. e. 6-hydroxy-7-methoxyquinazolin-4（ 3H）-one（ 1） was etherificated with N-（ 3-chloropropy1） morpholin（ 2） in ionic liquid to form intermediate 3,then chlorination and nucleophilic substitution reaction with 3-chloro-4-fluoroaniline were carried out to obtain target compound. The overall yield was 68. 7%. The influences of the molar ratio of 1 to 2,the amount of ionic liquid,the reaction time on the formation of the key intermediate 3 were investigated. The optimum reaction conditions were n（ 1） ∶ n（ 2） = 1. 0∶ 1. 2,m（ [BMIM]BF4） /m（ 1） = 5%,reaction temperature 95℃ and reaction time 5h. Under these conditions,the yield of 3 was 93. 6%. The advantages of the proposed synthetic route were mild reaction conditions,higher yields,shorter routes and easy to operation. It provides an experimental basis for the industrial production of gefitinib.

关 键 词：吉非替尼 离子液体 醚化 

分 类 号：TQ463.5[化学工程—制药化工]