Process for the preparation of 2-fluoroadenine
The present invention provides processes for the preparation of 2-fluoroadenine, as well as certain intermediates useful in the preparation of 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (EFdA): EFdA.
1. A process of preparing compound (4),
comprising:
(a) treating compound (2)
with a substituted amine reagent and a fluoride salt to provide compound (3), wherein the substituted amine reagent is trimethylamine; and
(b) treating compound (3) with an ammonia reagent to provide compound (4).
2. The process of claim 1 , wherein the fluoride salt in step (a) is an alkali metal fluoride or a C 1 -C 4 trialkylammonium fluoride.
3. The process of claim 2 , wherein the fluoride salt is potassium fluoride.
4. The process of claim 3 , wherein the potassium fluoride has a surface area of at least 0.4 m 2 /g.
5. The process of claim 1 , wherein the treating in step (a) is conducted in a dipolar aprotic solvent.
6. The process of claim 1 , wherein the ammonia reagent in step (b) is ammonia, aqueous ammonia, ammonia dissolved in an organic solvent, ammonium acetate, or ammonium carbonate.
7. The process of claim 1 , wherein steps (a) and (b) are conducted in a single vessel.
8. The process of claim 1 , wherein compound (2) is obtained by reacting compound (1)
with dihydropyran in the presence of an acid.
9. A process of preparing 2-fluoroadenine
comprising:
(a) treating compound (2)
with a substituted amine reagent and a fluoride salt to provide compound (3)
(b) treating compound (3) with an ammonia reagent to provide compound (4)
and
(c) treating compound (4) with an acid to provide 2-fluoroadenine.
10. A process for the preparation of 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)
(a) treating compound (2)
with a substituted amine reagent and a fluoride salt to provide compound (3);
(b) treating compound (3) with an ammonia reagent to provide compound (4)
and
(c) converting compound (4) to EFdA.