2-Bromo-3-nitrobenzoic acid → 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid

HRID 1267006Notes

Reaction equation

HRID 1267006 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:11].Br[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C(O)(C)C.CN1CCOCC1.[Cu].[Cu]I>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:13]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1

Participants

6

Reactant 2

HCID 684522-Bromo-3-nitrobenzoic acidHCID 1538381H-Indazol-4-amine, 1-methyl-

Product 1

HCID 109249982-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acidYield 5%

Reagents, catalysts & solvents 3

HCID 23978CopperCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 86583868isopropanol N-methylmorpholineSolvent

Procedure

A solution of 4-nitroindazole (prepared according to the literature procedures Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D. Org. Synth. Collect. Vol I, 20, 73-74.) (2.01 g, 12.3 mmol) was added slowly to a cold (ice/water), stirred suspension of NaH (440 mg, 18.4 mmol) in DMF (20 mL) under N2. The mixture was stirred for 30 min, and a solution of MeI (1.91 g, 13.5 mmol) in DMF (10 mL) was then added. Workup gave 1-methyl-4-nitroindazole (1.79 g, 82%); mp (EtOAc/petroleum ether) 138-139° C. Hydrogenation of this (6.70 g, 37.9 mmol) in absolute EtOH (300 mL) in the presence of Pd/C (1.00 g) gave 4-amino-1-methylindazole (4.23 g, 76%). A mixture of 4-amino-1-methylindazole (4.10 g, 27.9 mmol) and 2-bromo-3-nitrobenzoic acid (6.86 g, 27.9 mmol) were then reacted in a mixture of isopropanol/N-methylmorpholine in the presence of copper powder and CuI as above, giving 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid (439 mg, 5 %); mp (EtOAc/n-hexane) 257-260° C.; Reductive cyclisation of 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid with NaBH4 in 2 M NaOH as above gave 3-methyl-3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid as a dark yellow solid (54%); mp (acetone) 320-323° C. [(CD3)2SO] δ 4.28 (s, 3 H, NCH3), 8.07 (t, J=7.9 Hz, 1 H, H-8), 8.10 (d, J=9.6 Hz 1H, H-4 or H-5), 8.39 (d, J=9.6 Hz 1H, H-4 or H-5), 8.52-8.60 (m, 2H, H-7 and H-9), 8.76 (s, 1 H, H-2), 14.90 (br s, 1 H, COOH).

Sources & evidence

ORD record
ord-3e47feed398d4cf9a67f907ba765ca1b
Source dataset
uspto-grants-2003_04
Patent number
US06552021B2

Reaction notes

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