4-Aminophenol → 4-(4-Aminophenoxy)-N-methylpicolinamide

HRID 1696445Notes

Reaction equation

HRID 1696445 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][NH:20][C:18]([C:14]1[CH:13]=[C:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1)=[O:19]

Participants

6

Reactant 4

HCID 4034-AminophenolHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 14768144-Chloro-N-methylpicolinamide

Product 1

HCID 166551294-(4-Aminophenoxy)-N-methylpicolinamideYield 71%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 4-aminophenol (9.6 g, 88 mmol) in anhydrous DMF (100 mL) was treated with NaH (5.28 g of a 60% dispersion, 132 mmol), and the reddish-brown mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-N-methylpicolinamide (15 g, 88 mmol) and K2CO3 (6.5 g, 44 mmol) and heated at 80° C. for 8 h. The mixture was cooled to RT and partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated to afford 4-(4-amino-phenoxy)pyridine-2-carboxylic acid methylamide (15 g, 71% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.71 (d, J=1.8 Hz, 1H), 8.43 (d, J=5.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.06-7.03 (m, 1H), 6.76 (dd, J=8.7 Hz, 4H), 5.15 (s, 2H), 2.76 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 244 (M+H+).

Workup

  1. temperatureheated at 80° C. for 8 h
  2. temperatureThe mixture was cooled to RT
  3. custompartitioned between EtOAc and brine
  4. extractionThe aqueous phase was extracted with EtOAc
  5. washThe combined organic layers were washed with brine (2×50 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-4ac2a45bdb0a4a2fb1313c891b96fdf6
Source dataset
uspto-grants-2012_04
Patent number
US08163756B2

Reaction notes

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