Optimized Synthesis of an Abemaciclib Intermediate: Improved Conditions for a Miyaura Borylation/Suzuki Coupling Process

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-11-07 DOI:10.1021/acs.oprd.4c0038110.1021/acs.oprd.4c00381

Michael P. Carroll*, Aobha Hickey, Ava Rogers, Cáoimhe J. Niland, Rachel A. O’Sullivan, Nachimuthu Muniraj, Kevin F. O’Sullivan, Patrick J. Guiry and Michael M. Murray,

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Abstract

Improved reaction conditions have been developed for a telescoped Miyaura borylation/Suzuki coupling process, which is utilized in the synthesis of an abemaciclib intermediate. Key improvements include the in situ generation of a lipophilic base and tailored ligand selection for each palladium-catalyzed step. Optimizing ligand choice significantly reduced aryl scrambling, a major source of impurities in the borylation step. Additionally, the process improvements led to shortened reaction times and lower palladium loadings, resulting in a more efficient, higher-yielding process.

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优化合成 Abemaciclib 中间体：Miyaura Borylation/Suzuki Coupling 过程的改进条件

我们为伸缩宫浦硼酸化/铃木偶联过程开发出了改进的反应条件，并将其用于阿贝昔利中间体的合成。主要的改进包括原位生成亲油性碱，以及为每个钯催化步骤量身定制配体选择。配体选择的优化大大减少了芳基扰乱，而芳基扰乱是硼酸化步骤中杂质的主要来源。此外，工艺改进还缩短了反应时间，降低了钯载量，从而实现了更高效、更高产的工艺。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.

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