Streamlined Synthesis of SHP2 Inhibitor GDC-1971 Enhanced by a Telescoped Schotten-Baumann S N Ar and Reactive Crystallization Cascade

• Published in: Organic process research & development Vol. 28; no. 7; pp. 2862 - 2874
• Main Authors: Sirois, Lauren E., White, Nicholas A., Shen, Jeff, Dalton, Derek M., Zell, Daniel, St-Jean, Frédéric, Gosselin, Francis
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19-07-2024
• Subjects: Buchwald–Hartwig amination; Schotten–Baumann conditions; C–N coupling; wet milling; reactive crystallization; nucleophilic aromatic substitution (S N Ar)
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00162

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.