Lauren E. Sirois*, Nicholas A. White, Jeff Shen, Derek M. Dalton, Daniel Zell, Frédéric St-Jean and Francis Gosselin,
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引用次数: 0
Abstract
An improved synthetic process for SHP2 inhibitor GDC-1971 (migoprotafib) was developed to address challenges associated with the scalability and robustness of a preliminary fit-for-purpose route. In the optimized four-step sequence, the target’s pyrazolopyrazine core was functionalized sequentially, starting with an efficient palladium-catalyzed C–N coupling of its iodide with 1,2,3,4-tetrahydro-1,5-naphthyridine. Next, a nucleophilic aromatic substitution by a chiral aminospiropiperidine fragment upon the chloropyrazine was conducted under safe, biphasic Schotten-Baumann conditions and with high enough chemoselectivity that the product could be telescoped to a subsequent protecting group removal step. Isolation of the intermediate GDC-1971 hydrochloride salt leveraged reactive crystallization, whereas crystallization of the final GDC-1971 free base featured a wet milling operation to ensure a uniform particle size distribution. All of these improved reactions and revised workups/isolations were conducted on a multikilogram scale to provide a high-quality product without the need for chromatographic purification.
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.