Process for Making Nucleoside Phosphoramidate Compounds

A process for making a compound of formula (i):

• wherein said process comprises the steps:
• (A) contacting a compound of Formula (ia):
• with an acid or a compound of formula (C1-C6 alkyl)3SiCl in an organic alcohol solvent of formula R4OH, for a time and at a temperature sufficient to provide a compound of Formula (ic):
• (B) contacting the compound of formula (ic), or a salt thereof, with a compound of formula (id):
• R2OP(O)Cl2 (id)
• in the presence of a non-nucleophilic base, in an organic solvent B, for a time and at a temperature sufficient to provide an intermediate compound of formula (ie):
• and
• (C) contacting the compound of formula (ie) with a compound of formula (if):
• R1—XH (if)
• wherein X is O, S or NH, in the presence of a non-nucleophilic base, in an organic solvent B′, for a time and at a temperature sufficient to provide a compound of formula (i′), wherein organic solvents B and B′ are each independently selected from an organic acetate, THF, DCM, MTBE, 2-methyltetrahydrofuran, hexanes, xylenes, acetonitrile and mixtures thereof, and wherein:
• R2 is selected from C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl, wherein said C6-C10 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 R5 groups;
• R3 is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R5 groups;
• R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, —(C1-C3 alkylene)m-C3-C7 cycloalkyl) and —(C1-C3 alkylene)m-(C6-C10 aryl);
• each occurrence of R5 is independently selected from —C1-C6 alkyl, halo, —OR6, —C(O)R6, —CO2R6, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
• each occurrence of R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —(C1-C3 alkylene)m-(C3-C7 cycloalkyl), —(C1-C3 alkylene)m-C6-C10 aryl), —(C1-C3 alkylene)m-(4 to 7-membered heterocycloalkyl), —(C1-C3 alkylene)m-(5- or 6-membered monocyclic heteroaryl) or —(C1-C3 alkylene)m-(9- or 10-membered bicyclic heteroaryl);
• and
• each occurrence of m is independently 0 or 1.

A process for making a compound of formula (ii):

• wherein said process comprises the steps:
• (A) contacting a compound of Formula (iia):
• with CDI, in the presence of a base in an organic solvent C, for a time and at a temperature sufficient to provide a compound of Formula (iib):
• (B) contacting the compound of formula (iib) with HCl or a compound of formula (C1-C6 alkyl)3SiCl to provide a compound of Formula (iic):
• wherein R7 is either H or a hydroxy protecting group;
• (C) protecting any free hydroxy groups in the compound of formula (iic) to provide a compound of formula (iid), wherein both R7 groups are a hydroxy protecting group.
• and
• (D) contacting the compound of formula (iid) with a base in an organic solvent C′ for a time and at a temperature sufficient to provide a compound of Formula (ii),
• wherein organic solvents C and C′ are each independently selected from toluene, DMF, acetic acid, DCM, MTBE, 2-methyltetrahydrofuran, xylenes, ethyl acetate, isopropyl acetate, acetonitrile, 1,4-dioxane, DME, THF, CPME and mixtures thereof.