Water → HCID 90426546, compound

HRID 2279044Notes

Reaction equation

HRID 2279044 reaction equation
[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].[C:33]([CH:37]1[CH2:39][O:38]1)([CH3:36])([CH3:35])[CH3:34].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:39][CH:37]([OH:38])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[O:16])=[O:10])[CH:7]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydride2×HCID 921742-tert-Butyloxirane3×HCID 90446814HCID 90446814, compound

Product 1

HCID 90426546HCID 90426546, compoundYield 7.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) was treated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred at RT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g, 1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight. Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heated at 60° C. for 7 h, cooled to RT, treated with additional NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with -(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide (29 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (d, J=2.7 Hz, 1 H), 8.41 (d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 4.84 (d, J=5.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 3.05 (m, 1 H), 0.87 (s, 9H); MS (ESI) m/z: (M+H+): 531.2.

Workup

  1. stirringstirred at RT for 1 h
  2. temperatureheated at 60° C. overnight
  3. temperaturethe mixture heated at 60° C. for 7 h
  4. temperaturecooled to RT
  5. stirringstirred for 20 min
  6. temperatureheated at 60° C. overnight
  7. temperatureThe mixture was cooled to RT
  8. extractionextracted with EtOAc (3×)
  9. washthe combined organics were washed with brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated to dryness
  12. custompurified via silica gel chromatography (EtOAc, MeOH/DCM)

Sources & evidence

ORD record
ord-d112b9a861ae4420b135c2d623c90c59
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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