Synthesis ( IF 2.2 ) Pub Date : 2019-04-16 , DOI: 10.1055/s-0037-1610706 Lingfeng Yin , Yongjun Mao 1 , Yaowei Liu , Lehao Bu , Long Zhang , Wenxin Chen
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Abstract
A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.
A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.
中文翻译：
通往图卡替尼的新合成路线
抽象的
描述了一种新的和改进的合成曲妥替尼的合成途径，涉及三种关键中间体。其中的第一个是4-（[1,2,4] triazolo [1,5 - a ] pyridin-7-yloxy）-3-methylaniline，以100克的规模制备，在5步和99个步骤中产率为33％纯度％。接下来，分离出N 4-（4-（[1,2,4]三唑并[1,5 - a ]吡啶-7-基氧基）-3-甲基苯基）喹唑啉-4,6-二胺，三步分离产率为67％步骤和> 99％的纯度。然后，在温和的条件下以两步制备产率为67％的4,4-二甲基-2-（甲硫基）-4,5-二氢恶唑三氟甲磺酸盐。最终，在九个步骤中以17％的产率和> 99％的纯度（HPLC）获得了图卡替尼。还报道了用于分离产物和该路线涉及的中间体的纯化方法。
描述了一种新的和改进的合成曲妥替尼的合成途径，涉及三种关键中间体。其中的第一个是4-（[1,2,4] triazolo [1,5 - a ] pyridin-7-yloxy）-3-methylaniline，以100克的规模制备，在5步和99个步骤中产率为33％纯度％。接下来，分离出N 4-（4-（[1,2,4]三唑并[1,5 - a ]吡啶-7-基氧基）-3-甲基苯基）喹唑啉-4,6-二胺，三步分离产率为67％步骤和> 99％的纯度。然后，在温和的条件下以两步制备产率为67％的4,4-二甲基-2-（甲硫基）-4,5-二氢恶唑三氟甲磺酸盐。最终，在九个步骤中以17％的产率和> 99％的纯度（HPLC）获得了图卡替尼。还报道了用于分离产物和该路线涉及的中间体的纯化方法。
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