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
Key words
grazoprevir - NS3/4a protease inhibitor - macrolactamization - Sonogashira reaction
Significance
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.
Comment
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.
