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

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.