Route Optimization of the Noncovalent Modulator of Hemoglobin PF-07059013 for Treatment of Sickle Cell Disease through a Palladium-Mediated C–O Coupling, Part II: Pilot Plant Scale Manufacture

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2023-05-04 DOI:10.1021/acs.oprd.3c00038

Cameron Abercrombie, Christopher P. Ashcroft, Matthew Badland, Aaron Baldwin, Livia T. Baldwin, Sarah Brisley, Wayne Callar, Pedro Daddario, Elaa Hilou, Chintelle James, Ruizhi Li, Yiyang Liu*, Sebastien Monfette, Jared L. Piper, Giselle Reyes, Hud Risley, Fabrice H. Salingue, Kudzai Saunyama and Michael G. Vetelino,

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引用次数: 0

Abstract

Herein, we report the optimization of the first process chemistry route for pilot-plant-scale manufacture of PF-07059013 (1), a noncovalent modulator of hemoglobin for the treatment of sickle cell disease. Five areas of improvement are discussed in detail, namely, an alternative synthetic sequence to install the pyridone functionality before benzylic ether formation, a shorter and safer route to quinoline fragment 9, a tosyl-swap strategy to avoid isolation of a thermally unstable tosylate intermediate, Pd-catalyzed C–O coupling with low catalyst loading and efficient Pd removal, and improved final isolation of the API freebase. The new route was executed in our pilot plant facility to deliver 76 kg of API.

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通过钯介导的C-O偶联治疗镰状细胞病的血红蛋白PF-07059013非共价调节剂的路线优化，第二部分:中试工厂规模生产

在此，我们报告了中试工厂规模生产PF-07059013(1)的第一个工艺化学路线的优化，PF-07059013是一种治疗镰状细胞病的非共价血红蛋白调节剂。详细讨论了五个方面的改进，即:在苯醚形成之前安装吡啶酮功能的替代合成序列，更短更安全的喹啉片段9路线，避免分离热不稳定的tosylate中间体的tosyl-swap策略，Pd催化的C-O偶联具有低催化剂负载和高效Pd去除，以及改进API freebase的最终分离。新路线在我们的试验工厂执行，交付76公斤API。

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.