Development of Scalable and Commercial Synthesis for GS-441524

GS-441524 is a broad-spectrum, direct-acting antiviral, and its structural simplicity and oral bioavailability make it a promising therapeutic candidate. It is the parent nucleoside of remdesivir and the active metabolite of obeldesivir. However, the lack of a scalable, impurity-controlled, and regulatory-compliant synthesis has hindered its pharmaceutical development. This study presents an optimized, high-yielding, and commercial synthesis for GS-441524, demonstrating scalability up to multikilogram production. The key steps include a Lewis acid lanthanide salt-promoted glycosylation reaction and a diastereoselective continuous flow cyanation step with a 4-stream system, enhancing safety and reproducibility while achieving up to 94:6 diastereoselectivity and consistent yields at >60 kg scale. Furthermore, the development of an effective crystallization process controls the impurities to below 0.1A%, including potential genotoxic impurities (GTIs), during the isolation of the intermediate GS-441524 HCl salt. Additionally, two polymorphs were identified for GS-441524, with the most stable polymorph isolated using an in situ massive seed generation technique, effectively generating the desired target polymorph for the API. The process was demonstrated on several tens of kilograms with a 42% overall yield starting from 2, confirming its robustness and scalability, and provides a comprehensive and practical synthetic route for the manufacturing of GS-441524 as a drug substance compliant with regulatory guidelines.