Tetrahydrofuran → 6-Ethyl-5-[[2-(1-methyl-1h-pyrazol-4-yl)-4-pyridinyl]oxy]-2-pyridinamine

HRID 718176Notes

Reaction equation

HRID 718176 reaction equation
[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([N+:22]([O-])=O)[N:4]=1)[CH3:2].[NH4+].[Cl-].C1COCC1.CCOC(C)=O>CO.[Zn]>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[CH3:2]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 904036202-Ethyl-3-[[2-(1-methyl-1h-pyrazol-4-yl)-4-pyridinyl]oxy]-6-nitropyridine

Product 1

HCID 904038036-Ethyl-5-[[2-(1-methyl-1h-pyrazol-4-yl)-4-pyridinyl]oxy]-2-pyridinamineYield 51%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 887MethanolSolvent

Conditions

Temperature
77 °C

Procedure

2-Ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.1 g, 3.2 mmol) and NH4Cl (6.8 g, 128 mmol) were suspended in MeOH (12 mL) and THF (12 mL) at 0° C. The temperature was carefully maintained while Zn (2.1 g, 31.9 mmol) was added portion-wise over 20 min. The mixture was stirred vigorously for 12 h. EtOAc (75 mL) was added and solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (2×15 mL) and the combined filtrates were concentrated in vacuo. The residue was slurried with EtOAc (6 mL) and warmed to 77° C. for 5 min. Solids were collected by filtration, slurried with EtOAc (10 mL), and warmed to 77° C. for 5 min. The slurry was immediately filtered to collect solid product. The filtrates were combined and purified by silica gel chromatography (MeOH/EtOAc). Product material was combined and residual solvent was removed in vacuo to afford 6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.48 g, 51%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.7 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.50 (dd, J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.94 (s, 2H), 3.84 (s, 3H), 2.39 (q, J=7.5 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 296.2 (M+H+).

Workup

  1. customat 0° C
  2. additionwas added portion-wise over 20 min
  3. customsolids were removed by filtration through a pad of diatomaceous earth
  4. washThe filter cake was washed with EtOAc (2×15 mL)
  5. concentrationthe combined filtrates were concentrated in vacuo
  6. filtrationSolids were collected by filtration
  7. temperaturewarmed to 77° C. for 5 min
  8. filtrationThe slurry was immediately filtered
  9. customto collect solid product
  10. custompurified by silica gel chromatography (MeOH/EtOAc)
  11. customresidual solvent was removed in vacuo

Sources & evidence

ORD record
ord-fc09283f69f2423c98100d661648e60b
Source dataset
uspto-grants-2015_11
Patent number
US09193719B2

Reaction notes

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