基于三环二氮杂卓的 IDH1 突变抑制剂的工艺开发

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-06-06 DOI:10.1021/acs.oprd.4c00171

Matthew L. Maddess*, Ed Cleator*, Mariko Morimoto, Adrian Goodyear, Alejandro Dieguez-Vazquez, Andrew Gibb, Andy Kirtley, Melodie Christensen, Chaohui Song, Feng Peng, Mahbub Alam, Stephen P. Keen and Steven F. Oliver,

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引用次数: 0

摘要

本研究介绍了为改进一种抑制突变体 IDH1 的强效、选择性和脑穿透性三环二氮杂卓临床候选药物的合成途径而进行的工艺开发。对各种断开连接进行了评估，以确定片段偶联的优选序列。优化路线包括金属催化的 C-N 偶联/还原级联以形成中央二氮杂卓核心，改进之字形吗啉和环己基酸外围片段的入口，以及酰化、C-N 偶联和脱保护的高效终局序列。此外，还介绍了一种动态酰化过程，该过程可以在未受保护的二氮杂卓核心的 N6 处进行选择性酰化。

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Process Development of a Tricyclic Diazepine-Based IDH1 Mutant Inhibitor

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.

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.