Hydroxylamine → Ethyl 1-[4-amino-6-(2-methoxy-5-methylphenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

HRID 1255204Notes

Reaction equation

HRID 1255204 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[C:12]([N+:30]([O-])=O)[CH:11]=1.O.O.[Sn](Cl)Cl.NO.[Sn](Cl)Cl>CCOC(C)=O.[Pd].O.CN(C=O)C>[NH2:30][C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=1

Participants

9

Reactant 4

HCID 787HydroxylamineHCID 24479Stannous ChlorideHCID 61436Stannous chloride dihydrateHCID 67159086Ethyl 1-[6-(2-methoxy-5-methylphenyl)-4-nitropyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole 4-carboxylate

Product 1

HCID 67159525Ethyl 1-[4-amino-6-(2-methoxy-5-methylphenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of the title compound from Example 19 Step D (1.2 g, 2.7 mmol), DMF (15 mL), water (1.5 mL) and tin (II) chloride dihydrate (1.8 g, 7.9 mmol) was heated at 70° C. for 1.5 h, leading to reduction of the nitro group to the corresponding hydroxylamine. A second addition of tin (II) chloride dehydrate (2.4 g, 10.6 mmol) followed by heating at 100° C. overnight led to little progress. Water was added, and the reaction mixture was extracted with hexanes-EtOAc. The organic phase was separated and passed through a pad of silica gel. Hydrogenation using Pd-black (450 mg, 4.2 mmol) in EtOAc:EtOH (100 mL, 1:1 v/v) under 50 psi H2, followed by filtration and concentration, provided the title compound: LCMS m/z 421.6 [M+H]+; 1H NMR (400 MHz, acetone-d6) δ 8.09 (s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.26 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).

Workup

  1. temperatureby heating at 100° C. overnight
  2. extractionthe reaction mixture was extracted with hexanes-EtOAc
  3. customThe organic phase was separated
  4. filtrationEtOH (100 mL, 1:1 v/v) under 50 psi H2, followed by filtration and concentration

Sources & evidence

ORD record
ord-f2ed09f2a8fd4e2b871e266ed1616eb5
Source dataset
uspto-grants-2013_06
Patent number
US08455638B2

Reaction notes

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