【摘要】 目的 优化英菲格拉替尼的合成路线。方法 以对氟硝基苯为起始原料，经与N-乙基哌嗪亲核取代、还原反应得中间体4-（4-乙基哌嗪-1-基）苯胺（4）; 4,6-二氯嘧啶与甲胺经亲核取代反应得中间体6-氯-4-甲胺基嘧啶（5）;中间体4与中间体5经亲核取代反应得中间体N-[4-（4-乙基哌嗪-1-基）苯基]-N’-甲基嘧啶-4,6-二胺（6）;以3,5-二甲氧基苯胺为另一起始原料，依次经乙酰基保护、氯代、脱保护基反应后与氯甲酸苯酯缩合得中间体（2,6-二氯-3,5-二甲氧基苯基）氨基甲酸苯酯（10）。中间体6与10经亲核取代反应制得目标产物英菲格拉替尼。结果 英菲格拉替尼的化学结构经M S、¹H-NM R、¹³C-NM R及IR确证，总收率达到49.6%（以化合物2计），纯度达到99.38%（HPLC面积归一化法）。结论该工艺所采用的合成路线原料廉价易得，反应条件温和，整条路线避免了柱色谱方法纯化，后处理简单且绿色环保，所得中间体及目标产物纯度较高，为工业化生产奠定了基础。更多还原

【Abstract】 Objective To optimize the tw o synthetic routes for infigratinib involves tw o parallel pathw ays starting from distinct raw materials. Methods In the first pathw ay,4-fluoronitrobenzene underw ent nucleophilic substitution w ith N-ethylpiperazine follow ed by reduction to generate intermediate 4-（ 4-ethylpiperazin-1-yl） aniline（ 4）. Simultaneously,4,6-dichloropyrimidine reacted w ith methylamine via nucleophilic substitution to yield 6-chloro-4-（ methylamino） pyrimidine（ 5）. These tw o intermediates（ 4 and 5） w ere then coupled through nucleophilic substitution to form N-[4-（ 4-ethylpiperazin-1-yl） phenyl]-N’-methylpyrimidine-4,6-diamine（ 6）. In the second pathw ay,3,5-dimethoxyaniline w ere sequentially subjected to acetylation protection,chlorination,deprotection,and condensation w ith phenyl chloroformate,ultimately produced intermediate（ 2,6-dichloro-3,5-dimethoxyphenyl） carbamic acid phenyl ester（ 10）. The final step involved nucleophilic substitution betw een intermediates 6 and 10 to afford the target compound infigratinib. Results The chemical structure of infigratinib w as confirmed by M S,¹H-NM R,¹³C-NM R,and IR spectroscopy,achieving a total yield of 49. 6%（ based on compound 2） and a purity of99. 38%（ HPLC area normalization）. Conclusion This synthetic route demonstrates significant advantages,including the use of low-cost and readily available starting materials,mild reaction conditions,elimination of column chromatography for purification,simplified post-processing procedures,and high purity of intermediates and the final product,thereby laying a robust foundation for industrial-scale production.更多还原