Development of an Inherently Safe and Scalable Nickel-Catalyzed Borylation Process of an Aryl Sulfamate

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-12-12 DOI:10.1021/acs.oprd.4c00454

Matthew V. Joannou, Christopher Y. Bemis, Geoffrey E. Purdum, Candice L. Joe, Kyle Eckenroad, Sharla L. Wood, Shasha Zhang, Amy A. Sarjeant, Rebecca A. Green, Jeffrey Nye, Steven R. Wisniewski, Scott A. Savage

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Abstract

A safe and scalable synthesis of A, a key aryl boronate ester intermediate toward an immunology asset udifitimod, via a Ni-catalyzed Miyaura borylation is reported. High-throughput experimentation, design of experiment, and reagent stability/compatibility studies were used to optimize the reaction conditions and furnish the borylation of aryl sulfamate B in 80–85% yield and >98% purity/potency. Significant hydrogen off-gassing was observed during the reaction, metal remediation, and crystallization steps of the first-generation process, and efforts were made to quantify, understand, and mitigate this off-gassing to ensure a safe and reliable scale-up. Two multikilogram batches of the process were successfully run to afford A in an average 85% yield, >99% potency, and ≤28 ppm residual Ni. Using the mechanistic learnings from this work, a second-generation process was developed which significantly reduced hydrogen off-gassing at all steps of the process, as well as increasing final yield and reducing process mass intensity. This second-generation process was demonstrated on a 1 kg scale to afford the product in 90% yield, >99% purity/potency, and 50 ppm residual Ni.

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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.