Development of a Fluoride Scavenging Strategy to Allow a SNAr Reaction in a Glass-Lined Reactor toward the Synthesis of NBI-921352

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-08-21 Epub Date: 2026-07-09 DOI:10.1021/acs.oprd.6c00186

Ying Chen, John L. Tucker, Neill Penner, Keegan Start, Bradley Scott, Jean-Francois Vincent-Rocan, Brian M. Cochran

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引用次数: 0

Abstract

A practical fluoride scavenging strategy was developed to enable the execution of a fluoride-generating S_NAr reaction in a glass-lined reactor during the manufacture of NBI-921352. The DABCO-mediated substitution of an activated aryl fluoride with a secondary amine generates hydrogen fluoride, presenting a risk of glass etching during scale-up. Glass coupon studies confirmed measurable mass loss under both the standard and stressed reaction conditions. Screening of calcium salts identified calcium chloride as a soluble and reaction-compatible fluoride scavenger that preserved the reaction performance while preventing reactor damage. After optimization of downstream workup associated with calcium fluoride formation, the process was successfully implemented in a 4000 L glass-lined reactor under cGMP conditions, enabling the production of greater than 60 kg of the NBI-921352 intermediate without detectable glass etching.

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在玻璃衬里反应器中进行SNAr反应合成NBI-921352的氟清除策略的开发

在NBI-921352的制造过程中，为了在玻璃衬里的反应器中进行产生氟化物的SNAr反应，开发了一种实用的氟化物释放策略。dabco介导的用二胺取代活化的芳基氟生成氟化氢，在放大过程中存在玻璃蚀刻的风险。玻璃片研究证实了在标准和应力反应条件下均可测量的质量损失。钙盐的筛选表明，氯化钙是一种可溶的、与反应相容的氟清除剂，既能保持反应性能，又能防止反应器损坏。在优化了与氟化钙形成相关的下游工序后，该工艺在cGMP条件下的4000 L玻璃衬里反应器中成功实施，使生产超过60公斤的NBI-921352中间体没有检测到玻璃蚀刻。

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.