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

HRID 515031Notes

Reaction equation

HRID 515031 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 575153751-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine

Product 1

HCID 426288444'-((1S,2S)-2-{[(2S)-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-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine (the product of Example 1D, 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 separated organic layer was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.01 (m, 1H), 1.13 (m, 1H), 1.25 (d, J=6 Hz, 3H), 1.36 (m, 1H), 1.54 (m, 1H), 1.89 (m, 3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.65 (m, 1H), 2.79 (m, 1H), 3.27 (dd, J=12 Hz, J=6 Hz, 1H), 3.40 (m, 1H), 7.22 (d, J=9 Hz, 2H), 7.59 (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. washThe separated organic layer was washed with brine
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customchromatographed on silica gel eluting with 3% methanol (containing 10% concentrated NH4OH) in dichloromethane

Sources & evidence

ORD record
ord-c548579bbfc84b83a1ddca6b62c1a38f
Source dataset
uspto-grants-2015_08
Patent number
US09108948B2

Reaction notes

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