Processes for the preparation of Veliparib and intermediates thereof

• US 10,556,887 B2
• Filed: 10/23/2018
• Issued: 02/11/2020
• Est. Priority Date: 10/24/2017
• Status: Active Grant

• Current Assignee: Apotex Inc. (Apotex Holdings Incorporated)
• Original Assignee: Apotex Inc. (Apotex Holdings Incorporated)
• Inventors: Bodhuri, Prabhudas, Milnes, Kaarina K., Green, Melanie R. A., Weeratunga, Gamini, Gorin, Boris
• Primary Examiner(s): Shterengarts, Samantha L
• Application Number:
  US16/167,882
• Publication Number:
  US 20190119257A1
• Time in Patent Office: 476 Days
• Field of Search: None
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention provides processes for the preparation of Veliparib (1), as well as intermediates useful in the preparation thereof. In particular, processes are provided for the production of the compound of Formula (3), or a salt thereof, and cyclization to afford Veliparib (1).

Claims

1. A process for preparing Veliparib (1):

2. The process of claim 1, wherein G is CONH₂.

3. The process of claim 1, wherein G is R, R is CO₂R¹, and R¹ is H.

4. The process of claim 1, wherein G is R, R is CO₂R¹, and R¹ is an aliphatic group.

5. The process of claim 4, wherein R¹ is C1-C6 alkyl.

6. The process of claim 5, wherein R¹ is methyl.

7. The process of claim 6, wherein in step (ii), converting of the compound of Formula (2) to Veliparib (1) comprises treating the compound of Formula (2) with a source of ammonia.

8. The process of claim 7, wherein the source of ammonia is selected from the group consisting of ammonia gas, ammonium hydroxide and a solution of ammonia in methanol solvent.

9. The process of claim 1, wherein acid (A1) is a substantially anhydrous acid selected from the group consisting of carboxylic acids, sulfonic acids and mineral acids.

10. The process of claim 9, wherein acid (A1) is acetic acid.

11. The process of claim 10, wherein G in the compound of Formula (3) is CONH₂, and Veliparib (1) is provided as a diacetic acid salt.

12. A process for the preparing a compound of Formula (3):

13. The process of claim 12, wherein G is CONH₂.

14. The process of claim 13, wherein solvent (S2) is selected from the group consisting of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and N-methyl-2-pyrrolidone.

15. The process of claim 13, wherein the coupling is conducted at a temperature of at least about 50°

C.

16. The process of claim 13, wherein the coupling is conducted in the presence of a base (B2-B) that is selected from the group consisting of 4-(dimethylamino)pyridine and 1-methylimidazole.

17. A compound of Formula (3):

18. The compound of claim 17, or a salt thereof, wherein G is CONH₂ or CO₂R¹ and R¹ is C1-C6 alkyl.

19. The compound of claim 17, having the Formula (3-A):

20. The compound of claim 17, having the Formula (3-A):