Processes for the preparation of Veliparib and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10556887-B2
Application number	US-201816167882-A
Country	US
Kind code	B2
Filing date	Oct 23, 2018
Priority date	Oct 24, 2017
Publication date	Feb 11, 2020
Grant date	Feb 11, 2020

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).

First claim

What is claimed is:

1. A process for preparing Veliparib (1):

or a salt thereof, comprising
(i) cyclizing, in the presence of an acid (A1), a compound of Formula (3):

wherein
G is CONH 2 or R;
R is CO 2 R 1 or CN; and
R 1 is selected from the group consisting of H, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

to provide either Veliparib (1) when G is CONH 2 , or,
when G is R, a compound of Formula (2):

 and
wherein
R is CO 2 R 1 or CN; and
R 1 is selected from the group consisting of H, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, arylalkyl and substituted arylalkyl; and

(ii) when G is R, converting the compound of Formula (2) to Veliparib (1).

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

3. The process of claim 1 , wherein G is R, R is CO 2 R 1 , and R 1 is H.

4. The process of claim 1 , wherein G is R, R is CO 2 R 1 , and R 1 is an aliphatic group.

5. The process of claim 4 , wherein R 1 is C1-C6 alkyl.

6. The process of claim 5 , wherein R 1 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 CONH 2 , and Veliparib (1) is provided as a diacetic acid salt.

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

or a salt thereof, wherein
G is CONH 2 or R;
R is CO 2 R 1 or CN; and
R 1 is selected from the group consisting of H, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

comprising coupling, in the presence of a solvent (S2), of the compound of Formula (5):

with a compound of Formula (4):

or a salt thereof,
wherein
G is CONH 2 or R;
R is CO 2 R 1 or CN; and
R 1 is selected from the group consisting of H, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, arylalkyl and substituted arylalkyl.

13. The process of claim 12 , wherein G is CONH 2 .

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):

or a salt thereof, wherein
G is CONH 2 or R;
R is CO 2 R 1 or CN; and
R 1 is selected from the group consisting of H, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, arylalkyl and substituted arylalkyl.

18. The compound of claim 17 , or a salt thereof, wherein G is CONH 2 or CO 2 R 1 and R 1 is C1-C6 alkyl.

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

or a salt thereof, or having the Formula (3-BA1):

or a salt thereof.

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

or a salt thereof.

Assignees

• Apotex Inc

Inventors

• Bodhuri Prabhudas
• Milnes Kaarina K
• Green Melanie R A
• Weeratunga Gamini
• Gorin Boris

Classifications

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D403/04 Primary

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