N-{3-氯4-(3-氟苄基)氧基苯基}-6-碘喹唑啉-4-胺的合成工艺改进

摘要

An important intermediate of synthesizing new anti-cancer drugs of quinazoline derivatives,N- { 3-chloro-4-[ ( 3 -fiuorobenzyl) oxy ] phenyl } -6-iodoquinazolin-4-amine, was synthesized from 2-a-mino-5-iodobenzoic acid by a four-step reaction in overall yield of 77.9％. The structure was confirmed by1 H NMR and ESI-MS. The optimum reaction conditions of Williamson reaction at 35 ℃ for 12 h were as follows: 5 was 30 mmol, K2 CO3 was 24.8 g, 18-crown-6 was 0.79 g, KI was 0.49 g,acetone was 250 mL. The yield was 90.1％ under the conditions.%以2-胺基-5-碘苯甲酸为起始原料,经四步反应合成了新型喹唑啉类抗肿瘤药物拉帕替尼的关键中间体-N-{3-氯4-[(3-氟苄基)氧基]苯基}-6-碘喹唑啉-4-胺,总收率77.9%,其结构经1H NMR和ESI-MS确证.Williamson醚化反应的最佳条件为:4-(6-碘喹唑啉-4-基氨基)-2-氯苯酚(5)30.0 mmol,K2CO3 24.8 g,18-冠-6 0.79 g,KI 0.49 g,丙酮250 mL.于35℃反应12 h,收率90.1%.