Regioselective N-2 arylation of indazoles

Patent metadata

Field	Value
Publication number	US-9580407-B2
Application number	US-201314649299-A
Country	US
Kind code	B2
Filing date	Dec 3, 2013
Priority date	Dec 7, 2012
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

A novel process is provided for the efficient preparation of an asymmetric compound of structural formula I:

comprising a copper-catalyzed, carbon-nitrogen cross-coupling step. The process described as part of the present invention can be used to manufacture poly (ADP-ribose) polymerase (PARP) inhibitors, which may be useful for the treatment of cancer. In particular, the present invention describes a process for the manufacture of the PARP inhibitor, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

First claim

What is claimed is:

1. A process for preparing a compound of formula I:

wherein R 2 is hydrogen or an amine protecting group, comprising:
(a) carbon-nitrogen cross-coupling of (i) an indazole of formula II containing a protected amide:

wherein R 1 is C 1-8 alkyl, C 3-8 cycloalkyl, C 4-8 heterocyclyl, aryl, heteroaryl or arylC 1-8 alkyl, optionally substituted with one to three aryl, heteroaryl, C 3-8 cycloalkyl or OC 1-8 alkyl; and (ii) a piperidine compound of formula III:

wherein R 3 is a leaving group and R 2 is as provided above; in the presence of a catalytic amount of a copper salt, a suitable ligand, a base, and a solvent, forming a compound of formula IV:

wherein R 1 and R 2 are as provided above; and,
(b) de-protecting the amide of the compound of formula IV.

2. The process of claim 1 , wherein the copper salt is a Cu(I) or Cu(II) salt selected from CuI, CuCl, CuCl 2 , CuBr, CuBr.S(CH 3 ) 2 , CuBr 2 , CuF 2 , CuOAc, Cu(OAc) 2 , Cu 2 O, CuO, CuSO 4 , Cu(OTf) 2 , Cu(OMs) 2 , Cu(OTs) 2 , Cu(NO 3 ) 2 , or Cu(BF 4 ) 2 CuBr.

3. The process of claim 2 , wherein the copper salt is CuBr.

4. The process of claim 1 , wherein the copper salt is present in an amount less than or equal to about 10 mol % relative to the piperidine compound of formula III.

5. The process of claim 4 , wherein the copper salt is present in an amount less than or equal to about 5 mol % relative to the piperidine compound of formula III.

6. The process of claim 3 , wherein CuBr is present in an amount of about 5 mol % relative to the piperidine compound of formula III.

7. The process of claim 1 , wherein R 2 is an amine protecting group, and wherein the process further comprises de-protecting the piperidyl nitrogen of the compound of formula IV, forming the compound of formula V:

8. The process of claim 7 , wherein R 2 is an amine protecting group selected from formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzyl carbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitro-veratryloxycarbonyl, p-methoxybenzyl or tosyl.

9. The process of claim 8 , wherein R 2 is tert-butoxycarbonyl.

10. The process of claim 1 , wherein R 1 is C 1-8 alkyl, optionally substituted with one to three phenyl.

11. The process of claim 10 , wherein R 1 is tert-butyl, cumyl or trityl.

12. The process of claim 11 , wherein R 1 is tert-butyl.

13. The process of claim 1 , wherein R 3 is Br.

14. The process of claim 1 , wherein the ligand is selected from dimethylglycine, 8-hydroxyquinoline, phenanthroline, neocuproine, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2,2,6,6-tetramethyl-3,5-heptanedione, 2,6-dimethyl-3,5-heptanedione, 2-isobutyrylcyclohexanone, 2-acetylcyclohexanone, 2,4-pentanedione or 3,5-heptanedione.

15. The process of claim 14 , wherein the ligand is dimethylglycine or 8-hydroxyquinoline.

16. The process of claim 15 , wherein the ligand is 8-hydroxyquinoline.

17. The process of claim 1 , wherein the base is selected from K 2 CO 3 , K 3 PO 4 , K2HPO4, Cs 2 CO 3 , KHCO 3 , Na 2 CO 3 or NaHCO 3 .

18. The process of claim 17 , wherein the base is K 2 CO 3 .

19. The process of claim 1 , wherein the solvent is selected from dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), 1,3-dimethyl-2-imidazolidinone (DMI), N-methyl-2-pyrrolidone (NMP), sulfolane, pyridine, 2-picoline, 3-picoline, 4-picoline, toluene, o-xylene, m-xylene, p-xylene, dioxane, chlorobenzene or anisole, and combinations thereof.

20. The process of claim 19 , wherein the solvent is dimethylacetamide (DMAc).

21. The process of claim 1 , wherein the carbon-nitrogen cross-coupling of step (a) is performed at a temperature of between about 90° C. and about 130° C.

22. The process of claim 1 , wherein carbon-nitrogen cross-coupling of step (a) is performed in the presence of CuBr in the amount of about 5 mol % relative to the piperidine compound of formula IV, the ligand 8-hydroxyquinoline, the base K 2 CO 3 , and the solvent dimethylacetamide (DMAc), at a temperature of about 110° C.

23. The process of claim 22 , wherein R 1 is tert-butyl, R 2 is tert-butoxycarbonyl, and R 3 is Br, and wherein the process further comprises de-protecting the piperidyl nitrogen of the compound of formula IV, forming the compound of formula V:

24. A process for preparing a compound of formula VI:

comprising:
(a) carbon-nitrogen cross-coupling of (i) the indazole of formula VII and (ii) the piperidine compound of formula VIII, wherein Boc is tert-butoxycarbonyl:

in the presence of a catalytic amount of a copper salt, a suitable ligand, a base, and a solvent, forming the compound of formula IX:

and,
(b) de-protecting both the amide and the piperidyl nitrogen of the compound of formula IX in the presence of p-TsOH (aq), forming the compound of formula VI.

25. The process of claim 24 , wherein the carbon-nitrogen cross-coupling of step (a) is performed in the presence of CuBr in the amount of about 5 mol % relative to the piperidine compound of formula VIII, the ligand 8-hydroxyquinoline, the base K 2 CO 3 , and the solvent dimethylacetamide (DMAc), at a temperature of about 110° C.

Assignees

• Merck Sharp & Dohme

Inventors

• Chung Cheol K
• Scott Mark E
• Bulger Paul Gerard
• Belyk Kevin Michael
• Limanto John
• Humphrey Guy R

Classifications

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title