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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。
Objective To synthesize 3 related substances of lapatinib. Methods Lapatinib and 5- [4 - [[3-chloro-4 - [(3- fluorophenyl) methoxy] phenyl] amino] -6- quinazolin] -2-furaldehyde was reduced Amination was carried out to obtain the desired compound bis {{5- {4- {{3-chloro-4 - [(3- fluorobenzyl) oxy] phenyl} amino} quinazolin- - (methylsulfonyl) ethyl] amine (I); the ether bond of lapatinib was cleaved under the refluxing conditions of trifluoroacetic acid to obtain the related substance 2-chloro-4 - {{6 (II); 5- {4- [2-methyl-2- [3-Chloro-4 - [(3-fluorophenyl) methoxy] phenyl] amino] -6-quinazolin] -2-furaldehyde as the starting material, [5- (Aminomethyl) furan-2-yl] -N- {3-chloro-4- [(3-fluorobenzyl) oxy] phenyl} quinazolin-4-amine (III). RESULTS AND CONCLUSIONS The structures of related substances Ⅰ, Ⅱ and Ⅲ were confirmed by MS and 1H-NM R spectra. Ⅰ, Ⅱ and Ⅲ could be used as reference substance for quality control of lapatinib.