Anti-Viral Compounds
Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
1 - 4 . (canceled)
5 . A process of making methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate, or a pharmaceutically acceptable salt thereof, the process comprising:
reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with (2 S, 3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.
6 . The process of claim 5 , wherein the reacting step is performed in the presence of a peptide coupling reagent.
7 . The process of claim 6 , wherein the peptide coupling reagent is selected from the group consisting of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole (EDAC/HOBT), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), propane phosphonic acid anhydride (T3P), and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).
8 . (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).
9 . A process of making methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate, or a pharmaceutically acceptable salt thereof, the process comprising:
reacting a dimesylate with an amine to obtain a substituted pyrrolidine, wherein the dimesylate is (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate, the amine is 3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline, and the substituted pryrrolidine is 1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine.
10 . The process of claim 9 , further comprising:
reacting the substituted pyrrolidine with tert-butyl-2-carbamoylpyrrolidine-1-carboxylate to obtain a protected intermediate.
11 . The process of claim 10 , further comprising:
reducing, cyclizing, and deprotecting the protected intermediate to obtain (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole).
12 . The process of claim 11 , further comprising:
reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.
13 . (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate.
14 . 3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)aniline.
15 . 1-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-4-(4-fluorophenyl)piperidine.
16 . A process of making an HCV inhibitor, comprising reacting (S)-6,6′-((2R,5R)-1-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-1-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole) with an intermediate acid which is selected from:
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid,
(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid,
(S)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid,
(S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid,
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid,
(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid,
(2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid,
(S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid,
(S)-2-(methoxycarbonylamino)-2-((S)-tetrahydrofuran-3-yl)acetic acid,
(S)-2-(2,3-dihydro-1H-inden-2-yl)-2-(methoxycarbonylamino)acetic acid,
2-(tert-butoxycarbonylamino)acetic acid,
2-(methoxycarbonylamino)-3-methylbut-2-enoic acid,
(S)-tetrahydrofuran-2-carboxylic acid,
(S)-3-ethyl-2-(methoxycarbonylamino)pentanoic acid, or
(S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid.
17 . The process of claim 16 , wherein said intermediate acid is (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid.