Kinetic and Mechanistic Investigations to Enable a Key Suzuki Coupling for Sotorasib Manufacture─What a Difference a Base Makes

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2022-12-19 DOI:10.1021/acs.oprd.2c00332

James I. Murray*, Liang Zhang*, Adam Simon, Maria V. Silva Elipe, Carolyn S. Wei, Seb Caille and Andrew T. Parsons,

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引用次数: 6

Abstract

The process to manufacture sotorasib (AMG 510) employs a Suzuki–Miyaura reaction as a key step in the synthetic sequence. Detailed kinetic and mechanistic investigations into this process were utilized to identify the active catalytic species and rate-determining step, rationalizing current procedural requirements and process limitations. This knowledge was applied to demonstrate that simple alteration of the base (from KOAc to K₂CO₃) provided significant process improvements by shifting the rate-determining step and transmetalation pathways. Kinetic modeling was utilized for parameter optimization and resulted in significant reductions in both the Pd catalyst loading and equivalents of boronic acid as well as removing the requirement for slow reagent dosing. This report highlights the distinct mechanistic pathways that may occur upon alteration of the base in Suzuki–Miyaura coupling reactions.

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为Sotorasib制造提供关键铃木联轴器的动力学和力学研究──一个基座的作用有多大

生产sotorasib (AMG 510)的过程采用Suzuki-Miyaura反应作为合成序列的关键步骤。对这一过程进行了详细的动力学和机理研究，以确定活性催化物种和速率决定步骤，使当前的程序要求和工艺限制合理化。这些知识被用于证明碱基的简单改变(从KOAc到K2CO3)通过改变速率决定步骤和转化途径提供了显著的工艺改进。动力学建模用于参数优化，结果显著减少了钯催化剂负载和硼酸当量，并且消除了缓慢的试剂剂量要求。本报告强调了在Suzuki-Miyaura偶联反应中可能发生的碱基改变的独特机制途径。

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.