Acetamide → N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

HRID 2279056Notes

Reaction equation

HRID 2279056 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[C:31]([NH2:34])(=[O:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.CC#N.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([NH:34][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)(=[O:33])[CH3:32]

Participants

9

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 90426065N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

Product 1

HCID 90426862N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideYield 66%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

To a degassed solution of Example C3 (0.12 g, 0.278 mmol) in dioxane (3 mL) was added acetamide (0.066 g, 1.111 mmol), Cs2CO3 (0.091 g, 0.278 mmol), X-Phos (0.013 g, 0.028 mmol), Pd2(dba)3 (0.025 g, 0.028 mmol) and the mixture was stirred at 80° C. for 16 h. The mixture was diluted with EtOAc (5 mL) and filtered through a pad of diatomaceous earth. The filter pad was washed with EtOAc (3×8 mL). The combined filtrates were washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (0-5% MeOH/DCM) to afford a colorless foam. The foam was dissolved in MeCN-water and the solution was frozen and lyophilized to provide N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (83 mg, 66%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 10.54 (s, 1 H), 8.16 (d, J=5.7 Hz, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 7.60 (d, J=8.8 Hz, 1 H), 7.57 (d, J=2.4 Hz, 1 H), 6.61 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.78 (m, 5H), 3.48-3.33 (m, 4 H), 2.20 (s, 3 H), 2.02 (s, 3 H), 1.78-1.67 (m, 2 H), 1.64-1.58 (m, 2H); MS (ESI) m/z: 455.1 (M+H+).

Workup

  1. filtrationfiltered through a pad of diatomaceous earth
  2. washThe filter pad was washed with EtOAc (3×8 mL)
  3. washThe combined filtrates were washed with water and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by chromatography (0-5% MeOH/DCM)
  7. customto afford a colorless foam
  8. temperaturethe solution was frozen

Sources & evidence

ORD record
ord-03650b4a4c6542259369dff742449605
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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