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Details for Patent: 8,357,798

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Details for Patent: 8,357,798

Title:Process for preparing N-alkylated hydroxypyrimidinone compounds
Abstract: Potassium salts of Compound A and methods for their preparation are disclosed, wherein Compound A is of formula: ##STR00001## Compound A is an HIV integrase inhibitor useful for treating or prophylaxis of HIV infection, for delaying the onset of AIDS, and for treating or prophylaxis of AIDS.
Inventor(s): Belyk; Kevin M. (Somerset, NJ), Morrison; Henry G. (Simi Valley, CA), Jones; Philip (Rome, IT), Summa; Vincenzo (Rome, IT), Cooper; V. Brett (Hertfordshire, GB), Mahajan; Amar J. (Piscataway, NJ), Kumke; Daniel J. (Colts Neck, NJ), Tung; Hsien-Hsin (Edison, NJ), Wai; Lawrence (Scotch Plains, NJ), Pruzinsky; Vanessa (Metuchen, NJ), Pye; Philip (Guttenberg, NJ), Angelaud; Remy (Union, NJ), Mancheno; Danny (Rego Park, NY)
Assignee: Merck Sharp & Dohme Corp. (Rahway, NJ)
Filing Date:Jun 04, 2010
Application Number:12/793,801
Claims:1. A process for preparing a compound of Formula Q: ##STR00028## which comprises reacting an alkyl halide of formula R.sup.1X with a compound of Formula S: ##STR00029## in a polar aprotic solvent and in the presence of a base selected from a magnesium base and a calcium base; wherein R.sup.1 is C.sub.1-6 alkyl; R.sup.2 is O--C.sub.1-6 alkyl or N(R.sup.A)R.sup.B, wherein R.sup.A and R.sup.B are each independently H or C.sub.1-6 alkyl; R.sup.3 is H or C.sub.1-6 alkyl; L is C.sub.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.sup.X).sub.2, wherein each R.sup.X is independently H or --O--C.sub.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.degree. C.

5. The process according to claim 1, wherein the alkyl halide of formula R.sup.1X 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.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl, (2) --C(.dbd.O)--C.sub.1-4 alkyl, (3) --C(.dbd.O)--CF.sub.3, (4) --C(.dbd.O)--CCl.sub.3, (5) --C(.dbd.O)--CH.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl, (6) --C(.dbd.O)--O--C.sub.1-4 alkyl, (7) --C(.dbd.O)--O--CH.sub.2--CH.dbd.CH.sub.2, and (8) --C(.dbd.O)--O--CH.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl.

8. The process according to claim 1, wherein the compound of Formula Q is a compound of Formula Q-A: ##STR00030## the compound of Formula S is a compound of Formula S-A: ##STR00031## 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.sub.3I; the magnesium base is Mg(OCH.sub.3).sub.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.degree. 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: ##STR00032## and the compound of Formula Q-A is Compound f: ##STR00033##

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.sup.X).sub.2, wherein each R.sup.X is independently H or --O--C.sub.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.degree. C.; the alkyl halide of formula R.sup.1X 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.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl, (2) --C(.dbd.O)--C.sub.1-4 alkyl, (3) --C(.dbd.O)--CF.sub.3, (4) --C(.dbd.O)--CCl.sub.3, (5) --C(.dbd.O)--CH.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl, (6) --C(.dbd.O)--O--C.sub.1-4 alkyl, (7) --C(.dbd.O)--O--CH.sub.2--CH.dbd.CH.sub.2, and (8) --C(.dbd.O)--O--CH.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl.

13. The process according to claim 12, wherein: the base comprises a magnesium base which is Mg(R.sup.X).sub.2, wherein each R.sup.X is independently --O--C.sub.1-4 alkyl; the polar aprotic solvent comprises a N,N-di-(C.sub.1-3 alkyl)-C.sub.1-3 alkylamide, a N--(C.sub.1-3 alkyl)pyrrolidone, or a di-(C.sub.1-3 alkyl)sulfoxide; the reaction is conducted at a temperature in a range of from about 15 to about 80.degree. C.; the alkyl halide of formula R.sup.1X 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.sup.1 is C.sub.1-3 alkyl; R.sup.2 is O--C.sub.1-3 alkyl; R.sup.3 is H or C.sub.1-3 alkyl; L is C.sub.1-3 alkylene; and W is --C(.dbd.O)--O--C.sub.1-4 alkyl, --C(.dbd.O)--O--CH.sub.2--CH.dbd.CH.sub.2, or --C(.dbd.O)--O--CH.sub.2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, --NO.sub.2, --C.sub.1-4 alkyl, or --O--C.sub.1-4 alkyl; and X is chlorine, bromine, or iodine.
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