Process for preparing 5-alkyl-7H-pyrrolo[2,3-d] pyrimindine-2-ols
View Patent ↗Methods of preparing 5-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ols are described, as are novel compounds useful in their preparation. A specific method encompassed by the invention is represented in the following scheme:
1. A method of preparing a compound of formula I:
or a salt thereof, which comprises contacting a compound of formula II:
with a compound of formula HCOOR 5 under basic conditions sufficient to provide the compound of formula I, wherein:
R 1 is hydrogen or optionally substituted alkyl, aryl, heterocycle, arylalkyl, or heterocycloalkyl; and
R 5 is optionally substituted alkyl, aryl, or arylalkyl.
2. The method of claim 1 , wherein the compound of formula II is prepared by contacting a compound of formula III:
with cyanoacetamide under conditions sufficient to provide the compound of formula II, wherein:
R 2 and R 3 are each independently hydrogen or R 4 CO—, or are taken together with the nitrogen atom to which they are attached to provide a heterocycle; and
R 4 is optionally substituted alkyl, aryl, arylalkyl, alkoxy, or aryloxy.
3. The method of claim 1 , wherein the basic conditions are afforded by a base in a solvent.
4. The method of claim 3 , wherein the base is a metal hydroxide, metal alkoxide, metal amide, or mixture thereof.
5. The method of claim 4 , wherein the metal hydroxide is lithium hydroxide, sodium hydroxide, or potassium hydroxide.
6. The method of claim 4 , wherein the metal alkoxide is lithium methoxide, sodium methoxide, or sodium ethoxide.
7. The method of claim 4 , wherein the metal amide is lithium hexamethyldisilazide.
8. The method of claim 3 , wherein the solvent is an alcohol, amide, ether, nitrile, or mixture thereof.
9. The method of claim 8 , wherein the alcohol is methanol or ethanol.
10. The method of claim 8 , wherein the amide is dimethylformamide, dimethylacetamide, or N-methylpyrrolidone.
11. The method of claim 8 , wherein the ether is tetrahydrofuran, dioxane, or dimethoxyethane.
12. The method of claim 8 , wherein the nitrile is acetonitrile.
13. The method of claim 8 , wherein the solvent comprises methanol and dimethylformamide.
14. The method of claim 2 , wherein the conditions sufficient to provide the compound of formula II comprise a base in a solvent.
15. The method of claim 14 , wherein the base is a metal hydroxide, metal alkoxide, metal amide, or mixture thereof.
16. The method of claim 15 , wherein the metal hydroxide is lithium hydroxide, sodium hydroxide, or potassium hydroxide.
17. The method of claim 15 , wherein the metal alkoxide is lithium methoxide, sodium methoxide, or sodium ethoxide.
18. The method of claim 15 , wherein the metal amide is lithium hexamethyldisilazide.
19. The method of claim 14 , wherein the solvent is an alcohol, amide, ether, nitrile, or mixture thereof.
20. The method of claim 19 , wherein the alcohol is methanol or ethanol.
21. The method of claim 19 , wherein the amide is dimethylformamide, dimethylacetamide, or N-methylpyrrolidone.
22. The method of claim 19 , wherein the ether is tetrahydrofuran, dioxane, or dimethoxyethane.
23. The method of claim 19 , wherein the nitrile is acetonitrile.
24. The method of claim 19 , wherein the solvent comprises methanol and dimethylformamide.
25. The method of claim 1 , wherein R 1 is hydrogen.
26. The method of claim 1 , wherein R 1 is lower alkyl.
27. The method of claim 2 , wherein R 2 is hydrogen.
28. The method of claim 2 , wherein R 3 is R 4 CO—.
29. The method of claim 28 , wherein R 4 is alkyl or aryl.
30. The method of claim 2 , wherein R 2 and R 3 taken together with the nitrogen atom to which they are attached form phthalimido or succinimido.
31. The method of claim 1 , wherein R 5 is lower alkyl or phenyl.
32. The method of claim 31 , wherein R 5 is ethyl.