Process for making nucleoside phosphoramidate compounds
View Patent ↗The present invention is directed to a process for making Nucleoside Phosphoramidate Compounds of formula (I): which are useful for the treatment and prophylaxis of HCV infection. The present invention is also directed to compounds that are useful as synthetic intermediates for making the compounds of formula (I).
1. A process for making a compound of Formula (I):
said process comprising contacting a compound of formula (i):
with a compound of formula (ii):
in the presence of an aluminum complex, iron complex, or zinc complex, and an optional non-nucleophilic base, in an organic solvent A for a time and at a temperature sufficient to form a compound of formula (I), wherein:
X is O, S or NH;
R 1 is selected from C 6 -C 10 aryl, 9 or 10-membered bicyclic heteroaryl, and 5 or 6-membered monocyclic heteroaryl, wherein said 5 or 6-membered monocyclic heteroaryl group, said 9 or 10-membered bicyclic heteroaryl group, and said C 6 -C 10 aryl group can each be optionally substituted with one or more R 5 groups;
R 2 is selected from C 6 -C 10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R 5 groups;
R 3 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl and benzyl, wherein said C 3 -C 7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R 5 groups;
R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, alkylene) m -(C 3 -C 7 cycloalkyl) and —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl);
each occurrence of R 5 is independently selected from —C 1 -C 6 alkyl, halo, —OR 6 , —C(O)R 6 , —CO 2 R 6 , —SR 6 , —C 1 -C 6 hydroxyalkyl, —C 1 -C 6 haloalkyl, —N(R 6 ) 2 , —S(O)R 6 , —S(O) 2 R 6 , —CN and —NO 2 ;
each occurrence of R 6 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl); and
each occurrence of m is independently 0 or 1;
and wherein organic solvent A is selected from toluene, THF, DCM, MTBE, DMF, propylene carbonate, DME, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 2-methyltetrahydrofuran, xylenes, ethyl acetate, NMP, anisole, isopropyl acetate, acetonitrile and mixtures thereof.
2. The process of claim 1 , wherein the compound of Formula (I) has the formula (I′):
and the compound of formula (i) has the formula (i′):
3. The process of claim 1 , wherein the process is carried out in the presence of an aluminum complex having the formula Al(—O—C 1 -C 6 alkyl) 3 , (C 1 -C 6 alkyl) 3 Al, (C 1 -C 6 alkyl) 2 AlCl, (C 1 -C 6 alkyl)AlCl 2 or AlCl 3 , and wherein the optional non-nucleophilic base is present and is an organic amine base.
4. The process of claim 1 , wherein X is O and R 1 is a C 6 -C 10 aryl group, optionally substituted with up to 5 groups, each independently selected from NO 2 and F.
5. The process of claim 4 , wherein X is O and R 1 is pentafluorophenyl.
6. The process of claim 5 , wherein R 3 is methyl, R 4 is isopropyl and R 2 is unsubstituted phenyl.
7. The process of claim 1 , wherein the compound of formula (I) that is made by said process is:
8. The process of claim 1 , wherein the compound of formula (I) that is made by said process is: