Potassium Carbonate → 4'-((1R,2R)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

HRID 73288Notes

Reaction equation

HRID 73288 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 27343264-Cyanophenylboronic acidHCID 692305391-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine

Product 1

HCID 441974534'-((1R,2R)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine (product of Example 3C, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound 1H NMR (300 MHz, CD3OD) 1.08 (m, 1H), 1.19 (m, 1H), 1.32 (d, J=6 Hz, 3H), 1.42 (m, 1H), 1.63 (m, 1H), 1.99 (m, 3H), 2.20 (m, 1H), 2.65 (m, 1H), 2.94 (m, 1H), 3.07 (m, 1H), 3.34 (dd, J=9 Hz, J=6 Hz, 1H), 3.51 (m, 1H), 7.24 (d, J=9 Hz, 2H), 7.60 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.

Workup

  1. temperaturecooled to ambient temperature
  2. custompartitioned between ethyl acetate (25 mL) and H2O (10 mL)
  3. extractionThe organic extraction
  4. washwas washed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customchromatographed on silica gel eluting with methanol (containing 10% concentrated NH4OH) in dichloromethane

Sources & evidence

ORD record
ord-9d2ef1e0b6d74f71be4e16b2f121f0bc
Source dataset
uspto-grants-2014_09
Patent number
US08829041B2

Reaction notes

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