达克替尼的合成工艺改进

Improved Synthesis of Dacomitinib

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%。

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%.