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

Patent metadata

Field	Value
Publication number	US-11028119-B2
Application number	US-201916717811-A
Country	US
Kind code	B2
Filing date	Dec 17, 2019
Priority date	Oct 29, 2013
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

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 the steps of:
(a) hydrogenating the starting compound of Formula IV:

wherein R is a hydroxyl protecting group,
to produce the compound of Formula IIa:

(b) reducing the compound of Formula IIa to produce the 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 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), acetic acid, trifluoroacetic acid, diisopropylethylamine, or ammonium hydroxide; and
wherein the hydrogenating in step (a) is carried out in the presence of a palladium catalyst.

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

3. The method of claim 2 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.

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

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

6. The method of claim 1 , wherein the final product is recrystallized or slurrified.

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

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

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

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

11. The method of claim 10 , wherein the particle size is reduced to about 50 μm or less.

12. The method of claim 1 , wherein the palladium catalyst is palladium on charcoal.

Assignees

• Otsuka Pharma Co Ltd

Inventors

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

Classifications

• C07H19/06 Primary

  Pyrimidine radicals · CPC title

• C07H1/06

  Separation; Purification · CPC title

• C07H17/02

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

• B01J31/0209

  Esters of carboxylic or carbonic acids · CPC title

• C07H19/04

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