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

Patent metadata

Field	Value
Publication number	US-9834576-B2
Application number	US-201415027022-A
Country	US
Kind code	B2
Filing date	Oct 29, 2014
Priority date	Oct 29, 2013
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention relates to methods and intermediates for synthesizing 2′-deoxy-2′,2′-difluorotetrahydrouridine compounds.

First claim

We claim:

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:

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Choi Hyeong-Wook
• Mathieu Steven
• Fang Frank
• Lewis Bryan Matthew

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title