Processes for the preparation of lesinurad and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10351537-B2
Application number	US-201815914165-A
Country	US
Kind code	B2
Filing date	Mar 7, 2018
Priority date	Mar 10, 2017
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

The present invention provides processes for the preparation of Lesinurad (1), as well as intermediates useful in the preparation thereof. In particular, the processes of the invention utilize novel intermediate compounds of Formulas (3) and (11), which provide improvements over the known processes for the preparation of Lesinurad (1).

First claim

What is claimed is:

1. A process for the preparation of Lesinurad (1):

or a salt thereof, the process comprising hydrolysis, in the presence of a solvent (S3), of a compound of Formula (2):

wherein
L is a linker corresponding with the backbone of either:
(a) a monomeric polyol having x hydroxyl substituents, each bonded to a different carbon atom;
(b) a water-soluble polymeric polyol having x mean hydroxyl substituents, each bonded to a different carbon atom; or
(c) a water-insoluble polymeric polyol suitable for use as a solid phase support having x mean hydroxyl substituents, each bonded to a different carbon atom; and

wherein the hydroxyl substituents of the polyol provide the oxygen atoms in the ester connection in the compound of Formula (2);
x and z1 are each at least 2; and
z1≤x.

2. The process of claim 1 , wherein L is a linker corresponding with the backbone of a monomeric polyol selected from the group consisting of C2-C10 aliphatic diols, C3-C10 aliphatic triols, C4-C20 aliphatic tetrols, saccharides and sugar alcohols.

3. The process of claim 2 , wherein the monomeric polyol is ethane-1,2-diol or propane-1,2,3-triol.

4. The process of claim 3 , wherein the monomeric polyol is ethane-1,2-diol and x and z1 are both 2.

5. The process of claim 1 , wherein the hydrolysis is conducted in the presence of a base (B2).

6. The process of claim 5 , wherein the base (B2) is an alkali metal hydroxide.

7. The process of claim 6 , wherein the base (B2) is lithium hydroxide.

8. The process of claim 1 , wherein the solvent (S3) is selected from the group consisting of water and ethers.

9. The process of claim 3 , wherein the compound of Formula (2) is prepared by a process comprising reacting, in the presence of a solvent (S2), a compound of Formula (3):

with a brominating agent,
wherein
L is a linker corresponding with the backbone of a monomeric polyol selected from the group consisting of ethane-1,2-diol and propane-1,2,3-triol; and
z is 2 or 3.

10. The process of claim 9 , wherein the brominating agent is selected from the group consisting of 1,3-dibromo-5,5-dimethylhydantoin and N-bromosuccinimide.

11. The process of claim 10 , wherein the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin.

12. The process of claim 9 , wherein the solvent (S2) is selected from the group consisting of acetonitrile, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl t-butyl ether, tetrahydrofuran, dioxane, dichloromethane, methanol, cyclohexane and hexane.

13. The process of claim 9 , wherein the compound of Formula (2) is not isolated.

14. The process of claim 9 , wherein the compound of Formula (3) is prepared by a process comprising reaction of a compound of Formula (5):

in the presence of a base (B1) and a solvent (S1), with a compound of Formula (4):

wherein
L is a linker corresponding with the backbone of a monomeric polyol selected from the group consisting of ethane-1,2-diol and propane-1,2,3-triol;
G 1 is a leaving group; and
y is 2 or 3.

15. The process of claim 14 , wherein G 1 is a halide.

16. The process of claim 14 , wherein the solvent (S1) is N,N-dimethylformamide.

17. A compound of Formula (3):

wherein
L is a linker corresponding with the backbone of a monomeric polyol selected from the group consisting of ethane-1,2-diol and propane-1,2,3-triol;
wherein the hydroxyl substituents of the polyol provide the oxygen atoms in the ester connection in the compound of Formula (3); and
z is 2 or 3.

18. A compound of Formula (2):

wherein
L is a linker corresponding with the backbone of either:
(a) a monomeric polyol having x hydroxyl substituents, each bonded to a different carbon atom;
(b) a water-soluble polymeric polyol having x mean hydroxyl substituents, each bonded to a different carbon atom; or
(c) a water-insoluble polymeric polyol suitable for use as a solid phase support having x mean hydroxyl substituents, each bonded to a different carbon atom; and

wherein the hydroxyl substituents of the polyol provide the oxygen atoms in the ester connection in the compound of Formula (2);
x and z1 are each at least 2; and
z1≤x.

19. The compound of claim 18 , wherein L is a linker corresponding with the backbone of a monomeric polyol selected from the group consisting of C2-C10 aliphatic diols, C3-C10 aliphatic triols, C4-C20 aliphatic tetrols, saccharides and sugar alcohols.

20. The compound of claim 19 , selected from:

Assignees

• Apotex Inc

Inventors

• Bodhuri Prabhudas
• Green Melanie R A
• Karadeolian Avedis
• Weeratunga Gamini
• Gorin Boris

Classifications

• C07D249/12 Primary

  Oxygen or sulfur atoms · CPC title