Process for preparing N-alkylated hydroxypyrimidinone compounds

1. A process for preparing a compound of Formula Q:

which comprises reacting an alkyl halide of formula R 1 X with a compound of Formula S:

in a polar aprotic solvent and in the presence of a base selected from a magnesium base and a calcium base; wherein

R 1 is C 1-6 alkyl;

R 2 is O—C 1-6 alkyl or N(R A )R B , wherein R A and R B are each independently H or C 1-6 alkyl;

R 3 is H or C 1-6 alkyl;

L is C 1-6 alkylene;

W is an amine-protective group; and

X is halogen.

2. The process according to claim 1 , wherein the base comprises a magnesium base which is Mg(R X ) 2 , wherein each R X is independently H or —O—C 1-6 alkyl.

3. The process according to claim 1 , wherein the polar aprotic solvent comprises a halogenated alkane, an ether, an ester, a tertiary amide, an N-alkylpyrrolidone, a sulfoxide, or a nitrile.

4. The process according to claim 1 , wherein the reaction is conducted at a temperature in a range of from about −20 to about 100° C.

5. The process according to claim 1 , wherein the alkyl halide of formula R 1 X is employed in an amount in a range of from about 0.5 to about 20 equivalents per equivalent of Compound S.

6. The process according to claim 1 , wherein the base is employed in an amount in a range of from about 0.5 to about 10 equivalents per equivalent of Compound S.

7. The process according to claim 1 , wherein W is selected from the group consisting of:

(1) —CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl,

(2) —C(═O)—C 1-4 alkyl,

(3) —C(═O)—CF 3 ,

(4) —C(═O)—CCl 3 ,

(5) —C(═O)—CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl,

(6) —C(═O)—O—C 1-4 alkyl,

(7) —C(═O)—O—CH 2 —CH═CH 2 , and

(8) —C(═O)—O—CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl.

8. The process according to claim 1 , wherein the compound of Formula Q is a compound of Formula Q-A:

the compound of Formula S is a compound of Formula S-A:

the alkyl halide is a methyl halide; and the base is a magnesium base.

9. The process according to claim 8 , wherein

the methyl halide is CH 3 I;

the magnesium base is Mg(OCH 3 ) 2 ;

the polar aprotic solvent is DMF, DMAC, N-methylpyrrolidone, N-ethylpyrrolidone, or DMSO;

the reaction is conducted at a temperature in a range of from about 0 to about 100° C.;

the methyl halide is employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound S-A; and

the magnesium base is employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound S-A.

10. The process according to claim 9 , wherein the compound of Formula S-A is Compound e:

and

the compound of Formula Q-A is Compound f:

11. The process according to claim 9 , wherein W is benzyl, acetyl, Boc, Cbz, Alloc, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, or 2,4-dichlorobenzyloxycarbonyl.

12. The process according to claim 1 , wherein:

the base comprises a magnesium base which is Mg(R X ) 2 , wherein each R X is independently H or —O—C 1-6 alkyl;

the polar aprotic solvent comprises a halogenated alkane, an ether, an ester, a tertiary amide, an N-alkylpyrrolidone, a sulfoxide, or a nitrile;

the reaction is conducted at a temperature in a range of from about −20 to about 100° C.;

the alkyl halide of formula R 1 X is employed in an amount in a range of from about 0.5 to about 20 equivalents per equivalent of Compound S;

the base is employed in an amount in a range of from about 0.5 to about 10 equivalents per equivalent of Compound S; and

W is selected from the group consisting of:

(1) —CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl,

(2) —C(═O)—C 1-4 alkyl,

(3) —C(═O)—CF 3 ,

(4) —C(═O)—CCl 3 ,

(5) —C(═O)—CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl,

(6) —C(═O)—O—C 1-4 alkyl,

(7) —C(═O)—O—CH 2 —CH═CH 2 , and

(8) —C(═O)—O—CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl.

13. The process according to claim 12 , wherein:

the base comprises a magnesium base which is Mg(R X ) 2 , wherein each R X is independently —O—C 1-4 alkyl;

the polar aprotic solvent comprises a N,N-di-(C 1-3 alkyl)-C 1-3 alkylamide, a N—(C 1-3 alkyl)pyrrolidone, or a di-(C 1-3 alkyl)sulfoxide;

the reaction is conducted at a temperature in a range of from about 15 to about 80° C.;

the alkyl halide of formula R 1 X is employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound S;

the base is employed in an amount in a range of from about 1 to about 5 equivalents per equivalent of Compound S; and

W is benzyl, acetyl, t-butyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, or 2,4-dichlorobenzyloxycarbonyl.

14. The process according to claim 1 , wherein:

R 1 is C 1-3 alkyl;

R 2 is O—C 1-3 alkyl;

R 3 is H or C 1-3 alkyl;

L is C 1-3 alkylene; and

W is —C(═O)—O—C 1-4 alkyl, —C(═O)—O—CH 2 —CH═CH 2 , or —C(═O)—O—CH 2 -phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, —NO 2 , —C 1-4 alkyl, or —O—C 1-4 alkyl; and X is chlorine, bromine, or iodine.