Pyridine → N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

HRID 2279026Notes

Reaction equation

HRID 2279026 reaction equation
[C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1.[F:23][C:24]1[C:30]([CH3:31])=[C:29]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)[CH:28]=[CH:27][C:25]=1[NH2:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:23][C:24]1[C:30]([CH3:31])=[C:29]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)[CH:28]=[CH:27][C:25]=1[NH:26][C:12]([N:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)[C:1]1=[O:2])=[O:16]

Participants

7

Reactant 5

HCID 1049PyridineHCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 667293732-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yloxy)anilineHCID 904259751-(Oxan-4-yl)imidazolidin-2-one

Product 1

HCID 86270039N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideYield 76%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Phosgene (20% in toluene, 0.798 mL, 1.508 mmol) was treated drop-wise with a solution of Example B1 (0.128 g, 0.754 mmol) and pyridine (0.244 mL, 3.02 mmol) in DCM (5 mL), stirred at RT for 10 min, then concentrated to dryness. The residue was dissolved in DCM (5 mL), treated drop-wise with a solution of 2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.15 g, 0.503 mmol) and DIEA (0.527 mL, 3.02 mmol) in DCM (5 mL) stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.188 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (d, J=2.7 Hz, 1 H), 8.33 (d, J=5.7 Hz, 1 H), 8.24 (s, 1 H), 8.05 (t, J=9.0 Hz, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.16 (d, J=2.4 Hz, 1 H), 6.98 (d, J=9.0 Hz, 1 H), 6.57 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.83 (m, 6 H), 3.82-3.77 (m, 2 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (dd, J=12.6, 10.8 Hz, 2 H), 2.05 (d, J=2.0 Hz, 3 H), 1.71 (m, 2 H), 1.59 (br d, J=12.3 Hz, 2H); MS (ESI) m/z: 495.2 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. dissolutionThe residue was dissolved in DCM (5 mL)
  3. stirringstirred at RT for 3 h
  4. additionThe mixture was treated with satd
  5. extractionNaHCO3, extracted with DCM (3×)
  6. dry with materialthe combined organics were dried over Na2SO4
  7. concentrationconcentrated to dryness
  8. custompurified via silica gel chromatography (MeOH/DCM)

Sources & evidence

ORD record
ord-dacdf8e3ab9241fa95a6e2a5962011d1
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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