拉帕替尼的合成工艺改进

Improvement of Synthesis Process of Lapatinib

目的改进拉帕替尼的合成工艺。方法以N-(3-氯-4-((3-氟苯基)甲氧基)苯基)-6-碘喹唑啉-4-胺为原料,经Suzuki偶联,再与对甲苯磺酸成单盐。再经加成,还原,与对甲苯磺酸成双盐。四氢呋喃/水中自然降温,生成拉帕替尼。结果通过熔点测定、HPLC、质谱、1H NMR、元素分析、红外分析、对甲苯磺酸含量和水分含量测定等方法确证目标物结构。结论本工艺操作简单,适合工业化生产。

Objective To improve the synthesis process of lapatinib. Methods With N-（3-chloro-4-（（3-fluorobenzyl） oxy）phenyl）-6-iodoquinazolin-4-amine as the starting material, single salt was prepared through reaction with p-toluene sulfonic acid after Suzuki cross-coupling reaction. After addition and reduction reaction, double salt was prepared through reaction with p-toluene sulfonic acid. Lapatinib was obtained by natural cooling in THF/H2O. Results The structure of lapatinib was verified by mp determination, HPLC, MS, 1H NMR, elemental analysis, IR and determination of p-toluene sulfonic acid and water. Conclusion The process is simple, and can be suitable for large- scale production.