1,2-Dimethoxyethane → 2-(1-(3'-fluoro-4'-(hydroxymethyl)-5'-(methylsulfonyl)biphenyl-4-yl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol

HRID 1916886Notes

Reaction equation

HRID 1916886 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.COCCOC.[F:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([S:49]([CH3:52])(=[O:51])=[O:50])[C:35]=1[CH2:53][OH:54].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])([CH3:19])[CH3:18])=[CH:6][CH:7]=2)[CH:37]=[C:36]([S:49]([CH3:52])(=[O:51])=[O:50])[C:35]=1[CH2:53][OH:54]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 66797188(2-Fluoro-6-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolHCID 667973732-(1-(4-bromophenyl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol

Product 1

HCID 498219792-(1-(3'-fluoro-4'-(hydroxymethyl)-5'-(methylsulfonyl)biphenyl-4-yl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-olYield 20.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a 50 mL round bottom flask was added 2-(1-(4-bromophenyl)-2-(2-(2-fluorophenyl)propan-2-yl)-1H-imidazol-4-yl)propan-2-ol (380 mg, 911 μmol), DME (25 mL) and H2O (6 mL). The solution was sparged with N2 for 10 min prior to addition of (2-fluoro-6-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (360 mg, 1.09 mmol), potassium carbonate (380 mg, 2.73 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (74 mg, 91 μmol). The reaction mixture was allowed to stir at 80° C. for 2 h. The cooled reaction solution was diluted with EtOAc (30 mL) and filtered through a Celite padded Buchner funnel. The filtrate was washed with aq NH4Cl (150 mL×2). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage SP-1, 25 g SiO2 column, gradient elution from 5% EtOAc to 100% EtOAc) to afford the title compound (100 mg, 20% yield). 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J=2 Hz, 1H), 7.51 (dd, J1=2 Hz, J2=10 Hz, 1H), 7.29 (d, J=9 2H), 7.08-7.16 (mult, 1H), 6.85-6.92 (mult, 3H), 6.77-6.84 (mult, 2H), 6.65 (s, 1H), 5.09 (d, J=6 Hz, 2H), 3.35 (s, 1H), 3.30 (2, 3H), 3.02 (t, J=6 Hz, 1H), 1.72 (s, 6H), 1.62 (s, 6H); 19F NMR (400 MHz, CDCl3) δ−112.1, −113.5 ppm; LCMS (ES) m/z=541.3 [M+H]+, 563.2 [M+Na]+.

Workup

  1. customThe solution was sparged with N2 for 10 min
  2. customThe cooled reaction solution
  3. filtrationfiltered through a Celite
  4. washThe filtrate was washed with aq NH4Cl (150 mL×2)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel flash chromatography (Biotage SP-1, 25 g SiO2 column, gradient elution from 5% EtOAc to 100% EtOAc)

Sources & evidence

ORD record
ord-f8022e64960143a7b941a09faa16eef6
Source dataset
uspto-grants-2013_12
Patent number
US08618154B2

Reaction notes

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