Process for the production of 2-C-methyl-D-ribonolactone

1. A process for preparing 2-C-methyl-D-ribonolactone comprising:

adding CaO to a solution of D-fructose at a molar ratio of CaO to D-fructose of from about 5 to 1 to about 1.8 to 1, wherein the reaction temperature is from about 23° C. to about 40° C.

2. The process of claim 1 , further comprising:

addition of CO 2 until the mixture is about pH 7; addition of oxalic acid until the mixture is about pH 2 to 3;

separation of any resulting solid and aqueous phases;

addition of an organic solvent to the aqueous phase;

separation of the organic and aqueous phases;

evaporation of the organic solvent of the organic phase, thereby isolating 2-C-methyl-D-ribono-lactone; and

optionally precipitating the 2-C-methyl-D-ribono-lactone from acetone.

3. The process of claim 2 , wherein the reaction time is from about 5 to about 25 hours.

4. The process of claim 1 wherein the 2-C-methyl-D-ribono-lactone is protected with a protecting group.

5. The process of claim 4 wherein the protected 2-C-methyl-D-ribono-lactone is 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribono-lactone.

6. The process of claim 1 further comprising reducing the 2-C-methyl-D-ribono-lactone with sodium bis(2-methoxyethoxy)aluminum hydride/ethanol.

7. The process of claim 4 further comprising reducing the 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribono-lactone with sodium bis(2-methoxyethoxy)aluminum hydride/ethanol to form 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose.

8. The process of claim 7 further comprising protecting the 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose with a protecting group to form a protected 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose.

9. The process of claim 8 , wherein the protected 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose is 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose.

10. The process of claim 4 , wherein the protecting group is selected from the group consisting of silyl, benzoyl, p-toluoyl, p-nitrobenzoyl, p-chlorobenzoyl, acyl, acetyl, —(C═O)-alkyl, and —(C═O)-aryl.

11. The process of claim 8 , wherein the protecting group is selected from the group consisting of silyl, benzoyl, p-toluoyl, p-nitrobenzoyl, p-chlorobenzoyl, acyl, acetyl, —(C═O)-alkyl, and —(C═O)-aryl.

12. The process of claim 4 , wherein the protecting group is —(C═O)-alkyl.

13. The process of claim 8 , wherein the protecting group is —(C═O)-alkyl.

14. The process of claim 8 , wherein the reactions are carried out in a solvent selected from the group consisting of water, toluene, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide and ethanol.

15. The process of claim 1 wherein the total time for synthesis is about 60 hours.

16. The process of claim 1 wherein the total time for synthesis is less than 60 hours.

17. The process of claim 8 wherein the total time for synthesis is from about 5 days to about 14 days.

18. The process of claim 8 wherein the total time for synthesis is from about 5 days to 10 days.

19. The process of claim 8 further comprising

reacting the protected 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose with an optionally protected activated nucleoside base, optionally in the presence of a Lewis acid, to form a D-2′,3′,5′-tri-O-benzoyl-2′-C-methyl-D-ribonucleoside product; and

optionally deprotecting the D-2′,3′,5′-tri-O-benzoyl-2′-C-methyl-D-ribonucleoside product.

20. The process of claim 19 , wherein the nucleoside base has been activated by reaction with a silylating agent.

21. The process of claim 20 , wherein the silylating agent is selected from the group consisting of N,O-bis(trimethylsilyl)acetamide, hexamethyldisilazane, chlorotrimethylsilane, or tert-butyldiphenylsilyl chloride.

22. The process of claim 21 , wherein the silylating agent is N,O-bis(trimethylsilyl)acetamide.

23. The process of claim 19 , wherein the Lewis acid is selected from the group consisting of SnCl 4 , BF 3 , AlCl 3 , TiCl 2 , TiCl 4 , FeCl 3 , SnCl 2 and any mixture thereof.

24. The process of claim 23 , wherein the Lewis acid is SnCl 4 .

25. The process of claim 19 , wherein the protected 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose is 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose and the optionally protected nucleoside base is benzoylcytosine.

26. The process of claim 19 , wherein the D-2′,3′,5′-tri-O-benzoyl-2′-C-methyl-D-ribonucleoside product is deprotected with sodium methoxide in methanol.

27. The process of claim 1 , wherein the molar ratio of CaO to D-fructose is about 3 to 1.

28. The process of claim 1 , wherein the molar ratio of CaO to D-fructose is about 2 to 1.

29. The process of claim 1 , wherein the molar ratio of CaO to D-fructose is about 1.8 to 1.

30. The process of claim 2 , wherein the total reaction time is about 22 hours.