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

Patent metadata

Field	Value
Publication number	US-10526362-B2
Application number	US-201715813743-A
Country	US
Kind code	B2
Filing date	Nov 15, 2017
Priority date	Oct 29, 2013
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

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, and
wherein the catalyst is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

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

3. The method of claim 1 , 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. 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.

6. The method of claim 5 , wherein the catalyst is about 1 mol % to about 20 mol % DBU.

7. The method of claim 6 , wherein the catalyst is about 5 mol % to about 10 mol % DBU.

8. The method of claim 7 , wherein the catalyst is about 5 mol % DBU.

9. The method of claim 5 , wherein the final product is recrystallized or slurrified.

10. The method of claim 5 , wherein step (d) is carried out in the presence of a solution comprising acetonitrile.

11. The method, of claim 5 , wherein step (b) is carried out in the presence of CeCl 3 .

12. The method of claim 5 , further comprising a step of reducing the particle size of compound 1.

13. The method of claim 12 , wherein the particle size is reduced to about 50 μm or less.

Assignees

• Otsuka Pharma Co Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07H19/06 Primary

  Pyrimidine radicals · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title