妥卡替尼的合成新工艺

New Synthetic Process of Tucatinib

开发妥卡替尼的新工艺路线并对其进行改进,重点合成其三个关建中间体。4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)-3-甲基苯胺(6)经5步反应制得,产率32.8%,纯度99.1%;N4-(4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)-3-甲基苯基)喹唑啉-4,6-二胺(15)经3步反应制得,产率67.0%,纯度99.5%;4,4-二甲基-2-(甲硫基)-4,5-二氢恶唑三氟甲磺酸盐(17)经2步反应制得,产率为67.2%;得出结论:妥卡替尼经9步反应制得,总收率16.7%,纯度>99.5%(HPLC),目标产物及中间体结构经1H-NMR、13 C-NMR和LC-MS确证。

New and improved synthetic route of tucatinib is described.Three key intermediates are prepared successfully.4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline(6)is prepared in 32.8%yield over 5 steps and 99.1%purity.N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine(15)is prepared in 67.0%yield over 3 stepsand99.5%purity.4,4-Dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate(17)is prepared in mild conditions in 67.2%yield over 2 steps.Inconclusion,Tucatinib is obtained in 16.7%yield over 9 steps and in>99.5%purity(HPLC).The structure of tucatiniband the intermediates are verified by 1H-NMR,13 C-NMR and LC-MS.