1303533-81-4

Ravidasvir hydrochloride (PPI-668 hydrochloride) is a pan-genotypic inhibitor for hepatitis C virus (HCV) NS5A protein. Ravidasvir hydrochloride inhibits the replication of HCV, with EC50 of 0.12, 0.01 and 1.14 nM, for HCV gt-1a, gt-1b, and gt-3a replicons, respectively. Ravidasvir hydrochloride exhibits good pharmacokinetic characters in rats[1].

Ravidasvir hydrochloride is an oral HCV NS5A inhibitor that blocks viral replication by inhibiting the NS5A protein.

Starting material: 2-bromonaphthalene; the core of the naphthalene-imidazole moiety was assembled from 2-bromonaphthalene in three steps: Friedel-Crafts acylation using chloroacetyl chloride and aluminum chloride afforded the α-chloroketone. Alkylation of the α-chloroketone with N-Boc-L-proline (41) afforded the diketone intermediate. Cyclization of the diketone intermediate to form imidazole 42 was performed by heating in the presence of ammonium acetate. Miyaura borylation of imidazole 42 afforded the corresponding boronic ester. The resulting boronic ester was coupled with benzimidazole 43 under Suzuki conditions to convergently assemble the benzimidazole-naphthalene-imidazole core 44. Removal of the Boc protecting group under acidic conditions followed by double acylation using N-Moc-L-valine (45) and EDCI afforded the ravidasvir free base. Treatment of the ravidasvir free base with hydrochloric acid followed by crystallization from ethanol and n-butyl acetate afforded ravidasvir hydrochloride (VI).

[1] Zhong M, et al., Discovery of ravidasvir (PPI-668) as a potent pan-genotypic HCV NS5A inhibitor. Bioorg Med Chem Lett. 2016 Sep 15;26(18):4508-4512. DOI:10.1016/j.bmcl.2016.07.066