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

HRID 1049248Notes

Reaction equation

HRID 1049248 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-].CCOC(C)=O>CO.C1COCC1.[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 3

HCID 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 51.3%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of crude 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.038 g, 3.19 mmol) in MeOH (12 mL) and THF (12 mL) was treated with NH4Cl (6.83 g, 128 mmol), cooled to 0° C., treated portion-wise with zinc dust (2.08 g, 31.9 mmol) and stirred overnight as the cooling bath expired. The mixture was treated with EtOAc, the solids removed via filtration through diatomaceous earth, washed well with warm EtOAc and the filtrate concentrated to dryness. The residue was treated with EtOAc, heated to near-reflux, filtered to remove solids and the filtrate concentrated to dryness. The collected solids were treated again with EtOAc, heated to reflux and filtered hot to afford a white solid. The concentrated filtrate was purified via silica gel chromatography (MeOH/EtOAc) and combined with the solid isolated above to afford 6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (483 mg, 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), 7.18-7.16 (m, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.50-6.49 (m, 1H), 6.36-6.34 (m, 1H), 5.95-5.93 (m, 2H), 3.84 (s, 3H), 2.40-2.38 (m, 2H), 1.04 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 296.2 (M+H+).

Workup

  1. customthe solids removed via filtration through diatomaceous earth
  2. washwashed well with warm EtOAc
  3. concentrationthe filtrate concentrated to dryness
  4. additionThe residue was treated with EtOAc
  5. temperatureheated
  6. temperatureto near-reflux
  7. filtrationfiltered
  8. customto remove solids
  9. concentrationthe filtrate concentrated to dryness
  10. additionThe collected solids were treated again with EtOAc
  11. temperatureheated
  12. temperatureto reflux
  13. filtrationfiltered hot
  14. customto afford a white solid
  15. customThe concentrated filtrate was purified via silica gel chromatography (MeOH/EtOAc)
  16. customisolated above

Sources & evidence

ORD record
ord-d9c848bceb954a69bd4572b66d5f643f
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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