Pinnick Oxidation on Scale: Process Development of a BDK Inhibitor

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-07-03 DOI:10.1021/acs.oprd.4c00177

Joel T. Arcari, Catherine Buckley, Leanne M. Buzon, Yongbo Dan, Timothy Houck, Zuxi Jin, Chao Li, Peifang Li, Kai Liu, Yiyang Liu*, Javier Magano, Luis A. Martinez-Alsina, Bao Nguyen, Robert Pearson, Jared L. Piper*, John A. Ragan, Matthew R. Reese, Wanli Tian, Jared Van Haitsma, Michael G. Vetelino and Yuan Zhang,

引用次数: 0

Abstract

The development of a safe and scalable Pinnick oxidation of an aldehyde to a carboxylic acid in the late-stage synthesis of a BDK inhibitor candidate, PF-07208254, is reported. Extensive process safety testing revealed a large exotherm with significant heat accumulation during oxidant addition, which was minimized through careful control of oxidant dosing, and higher dilutions ensured complete solubility of the reactants. The role of atmospheric oxygen in generating sulfuric acid in the product stream, leading to partial decomposition, was identified. The optimized process was safely executed on a kilogram scale to deliver high-quality API for toxicology and clinical studies.

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规模化品尼克氧化：BDK 抑制剂的工艺开发

本报告介绍了在 BDK 候选抑制剂 PF-07208254 的后期合成过程中，开发一种安全且可扩展的醛到羧酸的平尼克氧化法。广泛的工艺安全测试表明，在氧化剂添加过程中会出现大量放热和显著的热量积累，但通过仔细控制氧化剂的剂量，以及较高的稀释度确保反应物的完全溶解度，可将放热降至最低。确定了大气中的氧气在产品流中生成硫酸并导致部分分解的作用。优化后的工艺在公斤级规模上安全实施，为毒理学和临床研究提供了高质量的原料药。

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.