Synthesis of Grazoprevir, a Potent NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Synthesis of Natural Org

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F. XU*, J. KIM, J. WALDMAN, T. WANG, P. DEVINE (MERCK & CO., INC., RAHWAY, USA) Category Synthesis of Grazoprevir, a Potent NS3/4a Protease Inhibitor for the Treatment of Hepatitis C Virus Synthesis of Natural Org. Lett. 2018, 20, 7261–7265. Products and Potential Drugs Synthesis of Grazoprevir Key words

grazoprevir

NS3/4a protease HO inhibitor MeO O MeO O NH O macrolactamization Boc O O N ⋅t-BuNH NH 2 Sonogashira ⋅MsOH reaction HO 95:5 regioselectivity MeO N Cl B (1.1 equiv) D (1.05 equiv) MeO N O DBU (1.3 equiv) CuI (0.01 equiv) N Cl DMA, 45 °C, 35 h (PPh3)3PdCl2 (0.005 equiv) A then MsOH (1.3 equiv) N Cl DIPEA (2.0 equiv) MeCN, 40 °C, 16 h C MeOH, 35 °C, 5 h 78% (437 mmol scale) mp not reported 115 mmol scale

MeO O MeO O O N NH ⋅MsOH HATU (1.5 equiv) HO NH DIPEA (1.0 equiv) NH MeO N O MeO N O O O O DMAc–THF, 0 °C, 7 h O O 84% from C N N F mp not reported E mp not reported 1. H2 (50 psi), 5% Pd/C THF, 30 °C 87% (18 mmol scale) 2. NaOH (2.25 equiv) MeOH, 45 °C, 4 h 96% (158 mmol scale) O O O O O O H HO O S NH2⋅HOTs S N O O N N O H H N N ⋅0.5 H2O HN O H (1.1 equiv) HN O

MeO N O O EDC⋅HCl (1.3 equiv) MeO N O O THF, 15 °C, 3 h 94% (18 mmol scale) N N G Grazopravir mp not reported mp not reported

Significance: Grazoprevir is an NS3/4a protease Comment: The thermal instability of the free base This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. inhibitor. It was approved by the FDA in 2016 as a of alkyne D was a challenge in the Sonogashira re- combination drug with elbasvir (Zepatier®) for the action. By using methanol as solvent, catalyst sta- treatment of hepatitis C viral infections. The scheme bility and reactivity was improved as evinced by in- depicts the chemistry developed to conjoin the creased catalytic turnover at milder temperatures fragments A, B, D, and H on large scale (>100 kg) (35 °C). The free base of sulfonamide H was unsta- in 51% overall yield and >99.8% purity. ble 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.

SYNFACTS Contributors: Philip Kocienski Synfacts 01022019, 15(02), 0111 Published online: 18.01.20191861-19581861-194X