Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Department of Process Chemistry and Catalysis, F. Hoffmann-La Roche Ltd, Basel 4070, Switzerland.
Org Lett. 2023 May 19;25(19):3417-3422. doi: 10.1021/acs.orglett.3c00961. Epub 2023 May 10.
A chromatography-free asymmetric synthesis of GDC-6036 () was achieved via a highly atroposelective Negishi coupling of aminopyridine and quinazoline catalyzed by 0.5 mol % [Pd(cin)Cl] and 1 mol % (,)-Chiraphite to afford the key intermediate ()-. An alkoxylation of ()- with ()--methylprolinol () and a global deprotection generates the penultimate heterobiaryl intermediate . A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 ().
通过 0.5 摩尔%[Pd(cin)Cl]和 1 摩尔%（，）-Chiraphite 催化的氨基吡啶和喹唑啉的高对映选择性 Negishi 偶联反应，实现了无色谱分离的 GDC-6036（）不对称合成，得到关键中间体（）。（）-与（）--甲基脯氨酸（）的烷氧基化反应和全局脱保护作用生成了前体杂芳基中间体。通过逐步酰化/砜消除和最终癸二酸酯盐形成和结晶进行丙烯酰胺的可控安装，得到高纯度 GDC-6036（）。
