Cesium carbonate → 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one

HRID 41189Notes

Reaction equation

HRID 41189 reaction equation
[N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)[CH:18]=2)[O:15][C:14]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:13][C:12]3=[O:30])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:38][C:36]1[CH:37]=[C:32]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:19]2[C:17]2[CH:18]=[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:13][C:12]3=[O:30])[CH:33]=[C:34]([F:39])[CH:35]=1.[F:38][C:36]1[CH:37]=[C:32]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[C:17]2[CH:18]=[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:13][C:12]3=[O:30])[CH:33]=[C:34]([F:39])[CH:35]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 1363131-Bromo-3,5-difluorobenzeneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866724156-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one

Product 2

HCID 665579648-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-oneHCID 665592448-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-oneYield 149.9%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (296 g, 716 mmol), 1-bromo-3,5-difluorobenzene (173 g, 895 mmol) and cesium carbonate (700 g, 2148 mmol) suspended in dioxane (3 L) was bubbled with nitrogen for 10 minutes. diacetoxypalladium (8.04 g, 36 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (41.4 g, 72 mmol) were added and the mixture bubbled with nitrogen for 2 minutes then heated at 100° C. for 2 hours. Upon cooling to room temperature the mixture was partitioned between DCM (500 mL) and water (250 mL). The organic phase was washed with brine and dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a brown gum. The gum was purified by flash column chromatography on silica using gradient elution (0% methanol/DCM to 5% methanol/DCM). The desired product, 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (282 g, 75%), was thus isolated as a pale yellow dry film. Mass Spectrum: m/z [M+H]+=526. More material was made by repeating this reaction.

Workup

  1. customwas bubbled with nitrogen for 10 minutes
  2. customthe mixture bubbled with nitrogen for 2 minutes
  3. temperatureUpon cooling to room temperature the mixture
  4. customwas partitioned between DCM (500 mL) and water (250 mL)
  5. washThe organic phase was washed with brine
  6. dry with materialdried with magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customto give a brown gum
  10. customThe gum was purified by flash column chromatography on silica using gradient elution (0% methanol/DCM to 5% methanol/DCM)

Sources & evidence

ORD record
ord-6c347fd2053c4b53bdc6763a8606b949
Source dataset
uspto-grants-2013_09
Patent number
US08530470B2

Reaction notes

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