Processes for the preparation of apalutamide and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10513504-B2
Application number	US-201916294259-A
Country	US
Kind code	B2
Filing date	Mar 6, 2019
Priority date	Mar 8, 2018
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

The present invention provides processes for the preparation of Apalutamide (1), as well as intermediates useful in the preparation thereof. In particular, the process of the invention utilizes the intermediate compound of Formula (2), wherein G is OH or a leaving group, which provides improvements over the known processes for the preparation of Apalutamide (1).

First claim

What is claimed is:

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

comprising reaction, in the presence of a solvent (S5), of a compound of Formula (2):

or a salt thereof, with the compound of Formula (7):

wherein
G is selected from the group consisting of OH and LG 3 ;
LG 3 is a leaving group selected from the group consisting of X and G 1 ;
G 1 is selected from the group consisting of OR and A;
X is halide;
A is selected from the group consisting of:

R is selected from the group consisting of a substituted or unsubstituted aliphatic group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 ring carbon atoms, and a substituted or unsubstituted arylalkyl group having 6 to 10 ring carbon atoms and 1 to 3 alkyl carbon atoms;
R a and R b are either (a) hydrogen, or (b) the groups R c and R d ;
R c and R d , taken together with the carbon atoms to which they are bonded form a ring selected from the group consisting of a substituted or unsubstituted aryl group having 6 to 10 ring carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 9 carbon atoms and at least one heteroatom selected from S, N and O, and a substituted or unsubstituted aliphatic group having 1 to 10 carbon atoms; and
R e is hydrogen or methyl.

2. The process of claim 1 , wherein G is LG 3 , and the compound of Formula (2) is the compound of Formula (2-B):

3. The process of claim 2 , wherein R is selected from the group consisting of a substituted or unsubstituted aryl group having 6 to 10 ring carbon atoms, and a substituted or unsubstituted arylalkyl group having 6 to 10 ring carbon atoms and 1 to 3 alkyl carbon atoms.

4. The process of claim 3 , wherein the solvent (S5) is selected from the group consisting of amides, dimethylsulfoxide and pyridine.

5. The process of claim 1 , wherein the solvent (S5) is pyridine.

6. The process of claim 5 , wherein G is OR and R is selected from the group consisting of C1-C4 alkyl and substituted phenyl, wherein the phenyl substituent is selected from the group consisting of NO 2 , chloride and fluoride.

7. The process of claim 6 , wherein G is methoxy.

8. The process of claim 2 , wherein the compound of Formula (2-B) is prepared by a process comprising displacement of the hydroxyl group of the carboxylic acid in a compound of Formula (2-A):

with LG 3 .

9. The process of claim 8 , wherein LG 3 is halide, and the displacement comprises reaction of the compound of Formula (2-A) with a halogenating agent selected from the group consisting of thionyl chloride, phosphorous trichloride and phosphorous pentachloride.

10. The process of claim 9 , wherein the halogenating agent is thionyl chloride.

11. The process of claim 8 , wherein LG 3 is G 1 and the displacement comprises activation of the carboxylic acid group of the compound of Formula (2-A) by reaction with a carboxylic acid activating agent, followed by reaction of the resulting active acid derivative with a compound of Formula (G 1 -H), wherein G 1 is selected from the group consisting of OR and A,
wherein
A is selected from the group consisting of:

R is selected from the group consisting of a substituted or unsubstituted aliphatic group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 ring carbon atoms, and a substituted or unsubstituted arylalkyl group having 6 to 10 ring carbon atoms and 1 to 3 alkyl carbon atoms;
R a and R b are either (a) hydrogen, or (b) the groups R c and R d ;
R c and R d , taken together with the carbon atoms to which they are bonded, form a ring selected from the group consisting of a substituted or unsubstituted aryl group having 6 to 10 ring carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 9 carbon atoms and at least one heteroatom selected from S, N and O, and a substituted or unsubstituted aliphatic group having 1 to 10 carbon atoms; and
R e is hydrogen or methyl.

12. The process of claim 11 , wherein G 1 is OR.

13. The process of claim 12 , wherein the carboxylic acid activating agent is selected from the group consisting of thionyl chloride, pivaloyl chloride, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl).

14. The process of claim 13 , wherein the carboxylic acid activating agent is thionyl chloride and R is a C1-C4 alkyl group.

15. The process of claim 14 , wherein R is methyl.

16. The process of claim 8 , wherein the compound of Formula (2-A) is prepared by a process comprising reaction, in the presence of a copper catalyst and a solvent (S1), of a compound of Formula (6):

with the compound of Formula (5):

or a salt thereof,
wherein
LG 1 is a leaving group.

17. The process of claim 16 , wherein LG 1 is bromide.

18. The process of claim 17 , wherein the copper catalyst is copper(I) iodide.

19. The process of claim 18 , wherein the reaction is conducted in the presence of a ligand (L1) selected from the group consisting of 2-acetylcyclohexanone, proline and ethylene glycol.

Assignees

• Apotex Inc

Inventors

• Bodhuri Prabhudas
• Ceccarelli Alfredo Paul
• Emmett Michael R
• Karadeolian Avedis
• Souza Fabio E S
• Weeratunga Gamini
• Gorin Boris

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07D233/56

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title