Process for making phosphoramidate protected nucleoside compounds

1. A process for making a compound of formula (II):

wherein said process comprising the step of contacting a compound of formula (I):

with a compound of formula (III):

in the presence of an aluminum complex having the formula the formula (C 1 -C 6 alkyl) 2 AlCl or Al(—O—(C 1 -C 6 alkyl)) 3 , and base 2,6-lutidine, in an organic solvent A for a time and at a temperature sufficient to form the compound of formula (II),

wherein:

X is O, S or CH 2 ;

B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups:

R 1 is selected from the group consisting of pentafluorophenyl, and 3-chloropyridyl;

R 2 is selected from the group consisting of 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 the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or 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 the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 14 cycloalkyl) and —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl);

each occurrence of R 5 is independently selected from the group consisting of —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 the group consisting of 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) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl);

R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, F, —CN, —N 3 , —N(R 9 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 7 cycloalkyl;

R 8 is selected from the group consisting of H and —C(O)R 13 ;

each occurrence of R 9 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 6 -C 10 aryl and C 3 -C 7 cycloalkyl;

R 10 , R 11 and R 12 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, halo, —OR 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —NHC(O)OR 14 , —NHC(O)N(R 14 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 14 ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 and —NHC(O)R 14 ;

each occurrence of R 13 is independently H or C 1 -C 6 alkyl;

each occurrence of R 14 is independently selected from the group consisting of H, C 1 -C 10 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.

2. The process of claim 1 , wherein the aluminum complex is (CH 3 ) 2 AlCl or Al(t-BuO) 3 .

3. The process of claim 1 , wherein the compound of formula (I) is:

wherein:

R 1 is pentafluorophenyl or 3-chloropyridyl;

R 3 is —C 1 -C 6 alkyl; and

R 4 is —C 1 -C 6 alkyl.

4. The process of claim 3 , wherein R 1 is pentafluorophenyl.

5. The process of claim 3 , wherein the compound of formula (I) is:

6. The process of claim 1 , wherein organic solvent A is THF.

7. The process of claim 1 , wherein the compound of formula (III) has the formula (IIIa):

wherein R 7 is selected from the group consisting of F, —CN, C 2 -C 6 alkynyl, —NH 2 and —N 3 ; and R 8 is H or —C(O)CH(CH 3 ) 2 .

8. The process of claim 7 , wherein R 7 is F, —C≡CH, —N 3 or —NH 2 ; and R 8 is H.

9. The process of claim 7 , wherein R 7 —CN and R 8 is —C(O)CH(CH 3 ) 2 .

10. The process of claim 1 , wherein the compound of formula (II) that is made is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.