Development of Scalable and Commercial Synthesis for GS-441524

Added on:
22 Jul, 2026

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.

  • Gajula P1
  • Vasilev M1
  • Li J1
  • Gangu A1
  • Lee D1
  • Tung H1
  • Mamunooru M1
  • Wang Z1
  • Chen A1
  • Rana J1
  • Yin J1
  • Regati S1
  • Karmakar A1
  • Ghosh A1
  • Chatterjee S1
  • Yadaw A1
  • Roy S1
  • Bandu R1
  • Dissanayake K1
  • Bietsch J1
  • Wannere C1
  • Krishnamurthy D1
  • Sirasani G1
  • Achanta S1
  • Armstrong J1
  • Huang J2
  • Sanderson P2
  • Qu B1
  • Senanayake C1
  •   1TCG GreenChem Inc., 701 Charles Ewing Blvd, Ewing, New Jersey 08628, United States
  • 2National Institutes of Health, National Center for Advancing Translational Sciences, 9800 Medical Center Drive-C221, Rockville, Maryland 20850, United States
Development of Scalable and Commercial Synthesis for GS-441524
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