Potassium Bicarbonate → 6-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one

HRID 714605Notes

Reaction equation

HRID 714605 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24]3)[CH3:22])=[CH:15][CH:14]=1)[CH2:7][C:6]2=[O:29].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)(O)[O-].[K+].Br[C:54]1[CH:66]=[CH:65][C:57]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][O:60]2)=[CH:56][CH:55]=1>O1CCOCC1.O.[Cl-].[Na+].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(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C@@H:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24]3)[CH3:22])=[CH:17][CH:18]=1)[CH:7]([C:54]1[CH:66]=[CH:65][C:57]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[CH:56][CH:55]=1)[C:6]2=[O:29]

Participants

9

Reactant 4

HCID 516893Potassium BicarbonateHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 46464362-(4-Bromophenoxy)tetrahydro-2H-pyranHCID 896196926-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)chroman-4-one

Product 1

HCID 896199056-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 218864351,4-Dioxane--water (1/1)SolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
110 °C

Procedure

6-Methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)chroman-4-one (420 mg, 1.06 mmol) was dissolved in 1,4-dioxane/water (4:1, 10 mL) and degassed twice. Pd2(dba)3 (11 mg, 0.011 mmol), tri-tert-butylphosphonium tetrafluoroborate (14 mg, 0.05 mmol), and potassium bicarbonate (85 mg, 0.8 mmol) were added and the reaction mixture was degassed twice. 2-(4-bromophenoxy)tetrahydro-2H-pyran (355 mg, 1.38 mmol) was then added and the reaction mixture was heated to 110° C. for 7 h. After cooling, ethyl acetate and brine were added to the reaction mixture and the two layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by purified by silica gel chromatography to afford 6-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one. LCMS: 572.1 (M+H)+.

Workup

  1. customdegassed twice
  2. customthe reaction mixture was degassed twice
  3. temperatureAfter cooling
  4. customthe two layers were separated
  5. washThe organic layer was washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude material was purified
  10. customby purified by silica gel chromatography

Sources & evidence

ORD record
ord-1852e726eb784255aec16460df921229
Source dataset
uspto-grants-2015_11
Patent number
US09187460B2

Reaction notes

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