Synthetic route to 2′-deoxy-2′,2′-difluorotetrahydrouridines

1. A method of producing compound 1:

or a salt thereof;

comprising precipitating or crystallizing compound 1 from a solution of compound 2:

in the presence of a catalyst,

wherein the solution comprises acetonitrile, acetone, tetrahydrofuran, dimethylsulfoxide (DMSO), or methanol, and

wherein the catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.

2. The method of claim 1 , wherein the catalyst is a Bronsted-Lowry base.

3. The method of claim 1 , wherein the catalyst is about 1 mol % to about 20 mol %.

4. The method of claim 1 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.

5. The method of claim 4 , wherein the catalyst is about 5 mol % DBU.

6. The method of claim 1 , wherein the catalyst is acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.

7. The method of claim 1 , wherein the solution comprises acetonitrile.

8. The method of claim 1 , wherein the solution comprises acetone, tetrahydrofuran, DMSO, or methanol.

9. A method of producing compound 1:

or a salt thereof;

comprising the steps of:

(a) hydrogenating a compound of Formula IV:

wherein R is a hydroxyl protecting group,

to produce a compound of Formula IIa:

(b) reducing the compound of Formula IIa to produce a compound of Formula IIIa:

(c) deprotecting the compound of Formula IIIa to produce compound 2:

and

(d) precipitating or crystallizing compound 2 in the presence of a catalyst to produce compound 1:

or a salt thereof,

wherein the catalyst is DBU, acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.

10. The method of claim 9 , wherein the catalyst is about 1 mol % to about 20 mol % DBU.

11. The method of claim 10 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.

12. The method of claim 11 , wherein the catalyst is about 5 mol % DBU.

13. The method of claim 9 , wherein the catalyst is acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide.

14. The method of claim 9 , wherein the final product is recrystallized or slurrified.

15. The method of claim 9 , wherein step (d) is carried out in the presence of a solution comprising acetonitrile.

16. The method of claim 9 , wherein step (d) is carried out in the presence of a solution comprising acetone or tetrahydrofuran.

17. The method of claim 9 , wherein step (b) is carried out in the presence of CeCl 3 .

18. The method of claim 9 , further comprising a step of reducing the particle size of compound 1.

19. The method of claim 18 , wherein the particle size is reduced to about 50 μm or less.

20. A compound of Formula I:

wherein R is a hydroxyl protecting group;

R 1 is H, a hydroxyl protecting group, or absent;

------ is a bond or absent; and

------ is absent when R 1 is H or a hydroxyl protecting group;

or a salt, or enantiomer, or diastereomer thereof.

21. The compound of claim 20 , having the structure of Formula II:

or a salt, or enantiomer, or diastereomer thereof.

22. The compound of claim 20 , having the structure of Formula III:

or a salt, or enantiomer, or diastereomer thereof.

23. The compound of claim 20 , having the structure of Formula Ia:

or a salt, or enantiomer, or diastereomer thereof.

24. The compound of claim 20 , wherein R 1 is H or absent.

25. The compound of claim 23 , having the structure of Formula IIa:

26. The compound of claim 23 , having the structure of Formula IIIa:

27. The compound of claim 25 , wherein the compound is compound 3:

28. The compound of claim 26 , wherein the compound is compound 4: