Synfacts 2019; 15(02): 0111
DOI: 10.1055/s-0037-1612028
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Grazoprevir

Philip Kocienski
Xu F. * Kim J, Waldman J, Wang T, Devine P. Merck & Co., Inc., Rahway, USA
Synthesis of Grazoprevir, a Potent NS3/4a Protease Inhibitor for the Treatment of Hepatitis C Virus.

Org. Lett. 2018;
20: 7261-7265
Further Information

Publication History

Publication Date:
18 January 2019 (online)



Grazoprevir is an NS3/4a protease inhibitor. It was approved by the FDA in 2016 as a combination drug with elbasvir (Zepatier®) for the treatment of hepatitis C viral infections. The scheme depicts the chemistry developed to conjoin the fragments A, B, D, and H on large scale (>100 kg) in 51% overall yield and >99.8% purity.



The thermal instability of the free base of alkyne D was a challenge in the Sonogashira reaction. By using methanol as solvent, catalyst stability and reactivity was improved as evinced by increased catalytic turnover at milder temperatures (35 °C). The free base of sulfonamide H was unstable at ambient temperature. Therefore, the EDC coupling was conducted at 0 °C by adding pyridine to a slurry of the acid G and the PTSA salt H in THF.