Process development to improve synthetic access to a potent, selective, and brain-penetrant tricyclic diazepine clinical candidate that inhibits mutant IDH1 is described. A variety of disconnections were evaluated to determine the preferred sequence of fragment coupling. The optimized route involves a metal-catalyzed C–N coupling/reductive cascade to form the central diazepine core, improved entries to both the zigzag morpholine and cyclohexyl acid peripheral pieces, and an efficient end-game sequence of acylation, C–N coupling, and deprotection. In addition, a dynamic acylation process that enables selective acylation at N6 of an unprotected diazepine core is described.

中文翻译：

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基于三环二氮杂卓的 IDH1 突变抑制剂的工艺开发


描述了改进合成获得有效、选择性和脑渗透性三环二氮杂卓临床候选药物的工艺开发，该候选药物可抑制突变 IDH1。评估了各种断开以确定片段偶联的首选顺序。优化的路线涉及金属催化的 C-N 偶联/还原级联以形成中央二氮杂卓核心，改进了锯齿形吗啉和环己酸外围片段的进入，以及有效的酰化、C-N 偶联、和去保护。此外，还描述了一种动态酰化过程，该过程能够在未受保护的二氮杂卓核心的 N6 处进行选择性酰化。