2′-deoxy-2′,2′-difluorotetrahydrouridines with high purity and methods of making the same

Patent metadata

Field	Value
Publication number	US-12187757-B2
Application number	US-202017766074-A
Country	US
Kind code	B2
Filing date	Oct 7, 2020
Priority date	Oct 8, 2019
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

The invention relates to methods of synthesizing 2′-deoxy-2′,2′-difluorotetrahydrouridine with increased purity and uniform particle size distribution. In particular, methods of the invention include crystallization and isolation procedures rendering synthetic reaction intermediates. The invention further includes compositions comprising the final compound in highly pure form, including lower number of impurities and lower levels of individual and total impurities.

First claim

What is claimed is:

1. 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 method comprises the following steps:
(i) wherein the hydrogenating step (a) is performed under hydrogen atmosphere with a palladium catalyst;
(ii) wherein the reducing step (b) is performed at a temperature of about −12° C. to about −5° C.;
(iii) wherein the deprotecting step (c) is performed in the presence of an organic base; and
(iv) wherein the work-up of the deprotected compound from deprotecting step (c) is performed under non-aqueous conditions.

2. The method of claim 1 , wherein the catalyst is about 1 mol % to about 20 mol % 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

3. The method of claim 2 , wherein the catalyst is about 5 mol % DBU.

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

5. The method of claim 1 , wherein the deprotecting step (c) further comprises a step of trituration.

6. The method of claim 1 , further comprising recrystallizing or slurrying compound 1.

7. The method of claim 6 , wherein the recrystallizing is performed at a pH of about 6.0 to about 7.4 and carried out by dissolving compound 1 at a temperature of about 50° C. to about 55° C. to produce a solution and then cooling the solution to about 5° C.

8. The method of claim 1 , wherein step (d) is carried out in the presence of a solution comprising acetonitrile.

9. The method of claim 1 , wherein step (d) is carried out in the presence of a solution comprising acetone or tetrahydrofuran.

10. The method of claim 1 , wherein step (b) is carried out in the presence of CeCl 3 .

11. The method of claim 1 , wherein the R is a benzoyl group.

12. The method of claim 1 , wherein the palladium catalyst used in step (i) is palladium on charcoal (Pd/C).

13. The method of claim 12 , wherein the amount of the Pd/C used in step (i) is a catalytic amount of not more than 0.1 part by weight per one part by weight of the compound of Formula IV.

14. The method of claim 12 , wherein the amount of the Pd/C used in step (i) is 0.025 to 0.05 parts by weight per one part by weight of the compound of Formula IV.

15. The method of claim 1 , wherein step (i) is performed in a mixed solvent comprising ethyl acetate, acetic acid, and water.

16. The method of claim 1 , wherein step (i) is performed under ambient or increased pressure.

17. The method of claim 1 , wherein step (i) is performed under increased pressure of 0.1 to 0.5 MPa.

18. The method of claim 1 , wherein the organic base used in step (iii) is one or more bases selected from the group consisting of DBU, triethylamine, DMAP, and DABCO.

19. The method of claim 1 , wherein the amount of the organic base used in step (iii) is 0.01 to 2.2 moles per mole of the compound of Formula IIIa.

20. The method of claim 1 , wherein the organic base used in step (iii) is DBU.

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Zuend Gemma
• Scott Ian
• Davar Nipun
• Annaka Kimiyoshi
• Miyake Masahiro
• Matsui Motoshi

Classifications

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/04 Primary

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

• B01J31/0247

  Imides, amides or imidates (R-C=NR(OR)) · CPC title

• B01J23/44 Primary

  Palladium · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title