Potassium Carbonate → N-(2,2-difluoroethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxamide

HRID 577943Notes

Reaction equation

HRID 577943 reaction equation
[F:1][CH:2]([F:20])[CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[C:13]([CH:18]=[O:19])[C:14](F)=[C:15]([F:16])[C:10]=2[O:9][N:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>C(#N)CCC.O.[Cl-].[Na+].O.C(OCC)(=O)C>[F:1][CH:2]([F:20])[CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[C:13]([CH:18]=[O:19])[C:14]([N:30]3[CH2:29][C@@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[C:15]([F:16])[C:10]=2[O:9][N:8]=1)=[O:6]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 11137133trans-2,6-DimethylmorpholineHCID 86658102N-(2,2-Difluoroethyl)-6,7-difluoro-5-formylbenzo[d]isoxazole-3-carboxamide2×

Product 1

HCID 86658101N-(2,2-difluoroethyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxamide

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 8008ButyronitrileSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

N-(2,2-Difluoroethyl)-6,7-difluoro-5-formylbenzo[d]isoxazole-3-carboxamide (Intermediate 243, 2.86 g, 9.86 mmol) was dissolved in butyronitrile (50 mL) and water (2.5 mL). Potassium carbonate (1.362 g, 9.86 mmol) and (2R,6R)-2,6-dimethylmorpholine (1.481 mL, 11.83 mmol) were added and the reaction was stirred at 90° C. for 4 hours. The crude reaction mixture was diluted with water, brine and ethyl acetate. The mixture was washed 2× with brine. The aqueous layer was back-extracted with ethyl acetate. The organic layers combined, dried over MgSO4 and concentrated. The residue was dissolved in DCM and purified by silica gel column chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated to give the title compound.

Workup

  1. customThe crude reaction mixture
  2. washThe mixture was washed 2× with brine
  3. extractionThe aqueous layer was back-extracted with ethyl acetate
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in DCM
  7. custompurified by silica gel column chromatography
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-7478b0cfc43d4f799e09f27716242dae
Source dataset
uspto-grants-2015_05
Patent number
US09040528B2

Reaction notes

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