以2- 溴-4- 甲氧基-5- 硝基苯甲腈( 2) 为起始原料，与3- 氯-4- 氟苯胺加成得到N-(3- 氯-4- 氟苯基) -2- 溴-4- 甲氧基-5- 硝基苯甲脒(3)，然后与甲酰胺环化得到N-(3- 氯-4- 氟苯基)-7- 甲氧基-6- 硝基喹唑啉-4- 胺(4)，接着用二氧化硫脲还原得到N-(3- 氯-4- 氟苯基)-7- 甲氧基喹唑啉-4,6- 二胺(5)，最后与(E)-4-(1- 哌啶基)-2- 丁烯酸酰化合成表皮生长因子受体(EGFR) 酪氨酸激酶抑制剂达克替尼，总收率为68.6％ ( 以2 计)，纯度99.2％。
Abstract
Dacomitinib, an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor, was synthesized from 2-bromo-4-methoxy-5-nitrobenzonitrile(2) by addition with 3-chloro-4-fluoroaniline to give N-(3-chloro-4- fluorophenyl)-2-bromo-4-methoxy-5-nitrobenzamidine(3), which was subjected to the cyclization with formamide to afford N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine(4). The subsequent reduction with thiourea dioxide gave N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4,6-diamine(5), followed by acylation with (E)-4- (piperidin-1-yl)-2-butenoic acid in an overall yield of 68.6％(based on compound 2) and purity of 99.2％.
关键词
达克替尼 /
抗肿瘤药 /
表皮生长因子受体酪氨酸激酶抑制剂 /
工艺改进
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Key words
dacomitinib /
antineoplastics /
EGFR tyrosine kinase inhibitor /
process improvement
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参考文献
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