Synthetic Route to 2'-Deoxy-2',2'-Difluorotetrahydrouridines

Patent metadata

Field	Value
Publication number	US-2016237107-A1
Application number	US-201415027022-A
Country	US
Kind code	A1
Filing date	Oct 29, 2014
Priority date	Oct 29, 2013
Publication date	Aug 18, 2016
Grant date	—

Abstract

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

First 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.

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 % 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).

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.

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:

29 . Compound 1:

or a salt thereof;
produced by the method of claim 1 .

30 . Compound 1 of claim 29 , having a purity of at least about 95%.

Assignees

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

• C07H1/06

  Separation; Purification · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title