Potassium Carbonate → 2-[(1R)-1-(4-Methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one

HRID 1749379Notes

Reaction equation

HRID 1749379 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([N:7]2[CH:6]([CH3:22])[C:5]3[C:9](=[CH:10][C:2]([C:32]4[CH:31]=[N:30][N:29]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][O:23]5)[CH:33]=4)=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH3:13])=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 510003841-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole2×HCID 904083936-Bromo-2-((R)-1-(4-methoxyphenyl)ethyl)-3-methylisoindolin-1-one

Product 1

HCID 904082912-[(1R)-1-(4-Methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-oneYield 89%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Combine 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (64 g, 177 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 g, 295 mmol), potassium carbonate (70 g, 506 mmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (9 g, 11 mmol), dioxane (800 mL), and water (212 mL) under nitrogen and heat to 70-75° C. for 16 hours. Add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 g, 54 mmol) and heat to 80-85° C. for 2 hours. Concentrate under reduced pressure to 200 mL, add ethyl acetate (500 mL) and water (500 mL), stir for 30 minutes, and filter the solids. Combine the solids and the organic layer and evaporate under reduced pressure. Dissolve the residue in dichloromethane and filter through a pad of silica gel. Wash the silica gel pad with dichloromethane/ethyl acetate (1:0) and then (2:1) and evaporate to dryness under reduced pressure. Slurry the solid in a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30° C. and filter to collect the solid to give the title compound as an off-white solid (68 g, 89%). ES/MS m/z: 432 (M+H).

Workup

  1. concentrationConcentrate under reduced pressure to 200 mL
  2. additionadd ethyl acetate (500 mL) and water (500 mL)
  3. filtrationfilter the solids
  4. customCombine the solids and the organic layer and evaporate under reduced pressure
  5. dissolutionDissolve the residue in dichloromethane
  6. filtrationfilter through a pad of silica gel
  7. washWash the silica gel pad with dichloromethane/ethyl acetate (1:0)
  8. custom(2:1) and evaporate to dryness under reduced pressure
  9. additionin a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30° C.
  10. filtrationfilter
  11. customto collect the solid

Sources & evidence

ORD record
ord-8ebf096599454e07895e301b7e32c8ca
Source dataset
uspto-grants-2015_10
Patent number
US09156824B2

Reaction notes

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