Hydrazine hydrate (1:1) → 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine

HRID 510362Notes

Reaction equation

[CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([C:16](=O)[CH3:17])[C:14]#[N:15].O.[NH2:20][NH2:21]>C(O)C>[CH3:17][C:16]1[C:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])=[C:14]([NH2:15])[NH:21][N:20]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of (1-cyano-2-oxopropyl)sodium (3.5 g, 33.2 mmol) in N,N-Dimethylformamide (25 mL) stirred under nitrogen at 0° C. was added a solution of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.0 g, 27.7 mmol) in 10 ml of DMF dropwise during 30 min. The reaction mixture was stirred at 40° C. for 2 hours. Then this solution was diluted with saturated ammonium chloride solution. This solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried, concentrated to dryness in vacuo. The crude product was purified with on a silica gel column to give 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3-oxobutanenitrile. (5.2 g, 74%). To a solution of 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}3-oxobutanenitrile (5.2 g, 20.4 mmol) in ethanol (400 mL) stirred under nitrogen at 20° C. was added neat hydrazine monohydrate (2.25 g, 30.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 100° C. for overnight. After cooled to room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified on a silica gel column (methanol/DCM gradient solvent system) to provide titled product. (2.16 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (s, 3H) 2.39 (s, 3H) 3.63 (s, 2H) 4.30 (br. s., 2H) 7.19 (d, J=7.58 Hz, 1H) 7.27 (t, J=7.71 Hz, 1H) 7.49 (s, 1H) 11.09 (br. s., 1H)

Workup

temperatureAfter cooled to room temperature
customthe reaction mixture was evaporated to dryness in vacuo
customThe residue was purified on a silica gel column (methanol/DCM gradient solvent system)

Sources & evidence

ORD record: ord-d02a2dc269874039b6c319ffd4183ecd
Source dataset: uspto-grants-2015_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09096605B2

Reaction notes

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