Sodium hydride → 3-Bromo-5-(((2-(1,1-dimethylethyl)-2'-fluoro-5'-(methyloxy)-1,1'-biphenyl-4-yl)methyl)oxy)pyridine

HRID 1662576Notes

Reaction equation

HRID 1662576 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=2)[CH:7]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 5995293-Bromo-5-hydroxypyridineHCID 577056714-(Chloromethyl)-2-(1,1-dimethylethyl)-2'-fluoro-5'-(methyloxy)-1,1'-biphenyl

Product 1

HCID 577058433-Bromo-5-(((2-(1,1-dimethylethyl)-2'-fluoro-5'-(methyloxy)-1,1'-biphenyl-4-yl)methyl)oxy)pyridineYield 61.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A dry round bottom flask containing 3-bromo-5-hydroxypyridine (0.1304 g, 0.749 mmol) (commercially available from Aldrich) in dry DMF (2 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (0.0361 g, 0.903 mmol) (60% wt in oil) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 8.10 (0.2301 g, 0.750 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and then extracted five times with EtOAc. The combined organic layers wee then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to afford 96.A (203.4 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (2H, dd, J=13.1, 2.2 Hz), 7.62 (1H, d, J=1.6 Hz), 7.57 (1H, m), 7.29 (1H, dd, J=7.6, 1.8 Hz), 7.10 (1H, d, J=7.4 Hz), 7.02 (1H, t, J=8.8 Hz), 6.95 (2H, m), 5.14 (2H, s), 3.80 (3H, s), 1.27 (9H, s).

Workup

  1. temperaturewas cooled in an ice bath
  2. waitAfter 10 minutes
  3. stirringto stir overnight at room temperature
  4. waitAfter 18 hours
  5. extractionextracted five times with EtOAc
  6. washThe combined organic layers wee then washed one time with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationThe solid was filtered off
  9. concentrationthe solvent was concentrated
  10. customThe residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane)

Sources & evidence

ORD record
ord-299e1914e1a44191b5a31d57ace1b08d
Source dataset
uspto-grants-2011_10
Patent number
US08030354B2

Reaction notes

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