抗肿瘤药拉帕替尼有关物质的合成

Synthesis of related substances of lapatinib

目的合成拉帕替尼的3个有关物质。方法拉帕替尼与5-[4-[[3-氯-4-[（3-氟苯基）甲氧基]苯基]氨基]-6-喹唑啉]-2-呋喃甲醛经还原胺化反应制得有关物质双{{5-{4-{{3-氯-4-[（3-氟苄基）氧基]苯基}氨基}喹唑啉-6-基}呋喃-2-基}甲基}[2-（甲磺酰基）乙基]胺（Ⅰ）;在三氟乙酸回流条件下拉帕替尼的醚键发生断裂制得有关物质2-氯-4-{{6-{5-{{[2-（甲磺酰基）乙基]氨基}甲基}呋喃-2-基}喹唑啉-4-基}氨基}苯酚（Ⅱ）;以5-[4-[[3-氯-4-[（3-氟苯基）甲氧基]苯基]氨基]-6-喹唑啉]-2-呋喃甲醛为原料,经肟化、还原制得有关物质6-[5-（氨基甲基）呋喃-2-基]-N-{3-氯-4-[（3-氟苄基）氧基]苯基}喹唑啉-4-胺（Ⅲ）。结果与结论有关物质Ⅰ、Ⅱ、Ⅲ的结构经MS、^1H-NM R谱确证,Ⅰ、Ⅱ、Ⅲ可作为拉帕替尼质量控制的杂质对照品。

To perform the quality control of lapatinib,three related substances were prepared.The process impurity bis[[5-[4-[[3-chloro-4-[（3-fluorobenzyl） oxy]phenyl]amino]quinazolin-6-yl]furan-2-yl]methyl][2-（methylsulfonyl） ethyl]amine（Ⅰ） has been directly prepared by reductive amination reaction using lapatinib and 5-[4-[[3-chloro-4-[（3-f1uorophenyl） methoxy]phenyl]amino]-6-quinazolinyl]-2-furaldehyde（2） as starting materials;The degradation impurity 2-chloro-4-[[6-[5-[[[2-（methylsulfonyl） ethyl]amino]methyl]furan-2-yl]quinazolin-4-yl]amino]phenol（Ⅱ） has been prepared in trifluoroacetic acid under reflux conditions,using lapatinib as starting material;The degradation impurity N-[3-ehloro-4-[（3-fluorobenzyl） oxy]phenyl]-6-[5-（amino methyl） furan-2-yl]-4-quinazolinamine（HI） has been prepared through two steps：oximation and reduction from the raw material 2.The structures of three impurities of lapatinib were verified by MS and ~1H-NMR.The three specified impurities can be used as the reference substances of the related substances in the quality control of lapatinib.