Claims
- 1. A method of preparing an N3-substituted-4-pyrimidone, the method comprising
(a) contacting a 4-pyrimidone with a non-aqueous base and an alkylating agent that includes an appropriately substituted alkyl moiety and a leaving group to form a reaction mixture; and (b) maintaining the reaction mixture for a time sufficient for the 4-pyrimidone to be substituted in the N3-position with the appropriately substituted alkyl moiety.
- 2. The method of claim 1, wherein the 4-pyrimidone is a 2-alkoxy-6-amino-4-pyrimidone.
- 3. The method of claim 2, wherein the 2-alkoxy-6-amino-4-pyrimidone is a 2-methoxy-6-amino-4-pyrimidone.
- 4. The method of claim 1, wherein the non-aqueous base is an alkali metal hydride.
- 5. The method of claim 4, wherein the alkali metal hydride is sodium hydride.
- 6. The method of claim 4, wherein the reaction mixture further includes an alkali metal halide.
- 7. The method of claim 5, wherein the reaction mixture further includes an alkali metal halide.
- 8. The method of claim 7, wherein the alkali metal halide is lithium bromide.
- 9. The method of claim 1, wherein the reaction mixture includes an aprotic polar organic solvent.
- 10. The method of claim 9, wherein the solvent is N,N-dimethylformamide.
- 11. The method of claim 1, wherein a sufficient time is 1 second to 240 minutes.
- 12. The method according to claim 1, wherein the amine salt is selected from the group consisting of a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, mesylate, maleate, fumarate, acetate, and trifluoroacetate salt of a free amine.
- 13. A method of preparing a 6-(substituted amino)uracil, the method comprising
(a) combining a 2-alkoxy-6-amino-4-pyrimidone with an amine compound selected from the group consisting of an amine salt and the corresponding free amine, to form a reaction mixture; and (b) heating the reaction mixture to at least 80° C. for a time sufficient for the 2-alkoxy-6-amino-4-pyrimidone and the amine compound to react to form said 6-(substituted amino)uracil.
- 14. The method of claim 13, wherein the 6-(substituted amino)uracil is an N3-substituted-6-(substituted amino)uracil.
- 15. The method of claim 14, wherein the N3-substituent is an optionally substituted alkyl.
- 16. The method of claim 13, wherein the amine compound is a free amine.
- 17. The method of claim 13, wherein the amine compound is an amine salt.
- 18. The method of claim 17, wherein step (a) further comprises adding the corresponding free amine to the reaction mixture.
- 19. The method of claim 18, wherein the reaction mixture consists essentially of an N3-substituted-2-methoxy-6-amino-4-pyrimidone, the amine salt, and the corresponding free amine.
- 20. The method of claim 19, wherein the amine salt is an aryl amine salt.
- 21. The method of claim 20, wherein the aryl amine salt is an optionally substituted aniline salt.
- 22. The method of claim 21, wherein the aniline salt is a 3,4-disubstituted aniline salt.
- 23. The method of claim 22, wherein the 3,4-disubstituted aniline salt is a salt of 3-methyl-4-ethyl aniline.
- 24. The method of claim 20, wherein the aryl amine salt is a benzylamine salt.
- 25. The method of claim 24, wherein the benzylamine salt is an optionally substituted benzylamine salt.
- 26. The method of claim 25, wherein the benzylamine salt is a 3,4-disubstituted benzylamine salt.
- 27. The method of claim 26, wherein the 3,4-disubstituted benzylamine salt is a salt of 3,4-dichlorobenzylamine.
- 28. The method of claim 13, wherein the amine salt is selected from the group consisting of a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, mesylate, maleate, fumarate, acetate, and trifluoroacetate salt of a free amine.
- 29. A method for preparing a 6-(substituted amino)uracil, the method comprising
(a) contacting a 2-alkoxy-6-amino-4-pyrimidone with a non-aqueous base and an alkylating agent that includes an appropriately substituted alkyl moiety and a leaving group, for a time sufficient to produce an N3-substituted-2-alkoxy-6-amino-4-pyrimidone; (b) isolating the N3-substituted-2-alkoxy-6-amino-4-pyrimidone; (c) combining the N3-substituted-2-alkoxy-6-amino-4-pyrimidone with an amine compound selected from the group consisting of an amine salt and the corresponding free amine, to form a reaction mixture; and (d) heating the reaction mixture to at least 80° C. for a time sufficient for the N3-substituted-2-alkoxy-6-amino-4-pyrimidone and the amine compound to react to form said 6-(substituted amino)uracil.
- 30. The method of claim 29, wherein the 2-alkoxy-6-amino-4-pyrimidone is a 2-methoxy-6-amino-4-pyrimidone.
- 31. The method of claim 29, wherein the non-aqueous base is an alkali metal hydride.
- 32. The method of claim 31, wherein the alkali metal hydride is sodium hydride.
- 33. The method of claim 29, wherein step (a) is conducted in the presence of an alkali metal halide.
- 34. The method of claim 33, wherein the alkali metal halide is lithium bromide.
- 35. The method of claim 29, wherein step (a) is conducted in an aprotic polar organic solvent.
- 36. The method of claim 35, wherein the solvent is N,N-dimethylformamide.
- 37. The method of claim 29, wherein the 6-(substituted amino)uracil is an N3-substituted-6-(substituted amino)uracil.
- 38. The method of claim 37, wherein the N3-substituent is an optionally substituted alkyl.
- 39. The method of claim 29, wherein the amine compound is a free amine.
- 40. The method of claim 39, wherein the reaction mixture consists essentially of an N3-substituted-2-methoxy-6-amino-4-pyrimidone and a free amine.
- 41. The method of claim 29, wherein the amine compound is an amine salt.
- 42. The method of claim 41, wherein the reaction mixture consists essentially of an N3-substituted-2-methoxy-6-amino-4-pyrimidone and an amine salt.
- 43. The method of claim 41, wherein step (c) further comprises adding the corresponding free amine to the reaction mixture.
- 44. The method of claim 43, wherein the reaction mixture consists essentially of an N3-substituted-2-methoxy-6-amino-4-pyrimidone, an amine salt, and the corresponding free amine.
- 45. The method of claim 44, wherein the amine salt is an aryl amine salt.
- 46. The method of claim 45, wherein the aryl amine salt is an optionally substituted aniline salt.
- 47. The method of claim 46, wherein the aniline salt is a 3,4-disubstituted aniline salt.
- 48. The method of claim 47, wherein the 3,4-disubstituted aniline salt is a salt of 3-methyl-4-ethyl aniline.
- 49. The method of claim 45, wherein the aryl amine salt is a benzylamine salt.
- 50. The method of claim 49, wherein the benzylamine salt is an optionally substituted benzylamine salt.
- 51. The method of claim 50, wherein the benzylamine salt is a 3,4-disubstituted benzylamine salt.
- 52. The method of claim 51, wherein the 3,4-disubstituted aniline salt is a salt of 3,4-dichlorobenzylamine.
- 53. The method according to claim 29, wherein the amine salt is selected from the group consisting of a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, mesylate, maleate, fumarate, acetate, and trifluoroacetate salt of a free amine.
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of priority from U.S. Provisional Patent Application No. 60/298,743, filed on Jun. 15, 2001, which is incorporated herein by reference in its entirety.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[0002] The invention described herein was supported in whole or in part by SBIR grant number A141260 from the National Institutes of Health. The government thus has certain rights in the invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60298743 |
Jun 2001 |
US |