4-Bromobenzoic acid → 1-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol

HRID 490713Notes

Reaction equation

HRID 490713 reaction equation
C(O[C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:5])C.Br[C:22]1C=CC(C(O)=O)=CC=1.[H-].[Na+].C(OC(=O)C(Cl)C(=O)C(C)C)C.C([O-])(=O)C.[NH4+]>CN(C=O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]([CH:4]([OH:5])[CH3:22])=[C:7]([CH:18]([CH3:19])[CH3:20])[N:8]=2)=[CH:16][CH:15]=1

Participants

7

Reactant 5

HCID 114644-Bromobenzoic acidHCID 24758Sodium hydrideHCID 517165Ammonium AcetateHCID 9877606Ethyl 2-chloro-4-methyl-3-oxopentanoateHCID 690532562-(4-Bromo-phenyl)4-isopropyl-oxazole-5-carboxylic acid ethyl ester

Product 1

HCID 587656641-[2-(4-Bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanolYield 55%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

2-(4-Bromo-phenyl)-4-isopropyl-oxazole-5-carboxylic acid ethyl ester A solution of 4-bromo-benzoic acid (34.0 g, 0.169 mol) in DMF (450 mL) is treated at ambient temperature portionwise with NaH (6.4 g, 0.16 mol, 60% oil dispersion). The suspension is heated to 90° C. and 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (27.7 g, 0.144 mol) is added neat. The remaining chloride is washed into the reaction flask using DMF (25 mL). The reaction mixture is stirred for 18 h, cooled, and treated with water (600 mL). The mixture is extracted with EtOAc (750 mL). The organic layer is washed with brine (2×250 mL), dried (Na2SO4), and concentrated to a foam (56 g). This diester is dissolved in acetic acid (500 mL), treated at ambient temperature with ammonium acetate (80 g, 1.0 mol), and heated at 120° C. for 20 h. The reaction mixture is cooled, concentrated, and partitioned between EtOAc (500 mL) and saturated NaHCO3 solution (3×125 mL). The organic layer is dried (Na2SO4), and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (6:1) to give the title compound (26.6 g, 55%).

Workup

  1. washThe remaining chloride is washed into the reaction flask
  2. temperaturecooled
  3. additiontreated with water (600 mL)
  4. extractionThe mixture is extracted with EtOAc (750 mL)
  5. washThe organic layer is washed with brine (2×250 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated to a foam (56 g)
  8. dissolutionThis diester is dissolved in acetic acid (500 mL)
  9. temperatureheated at 120° C. for 20 h
  10. temperatureThe reaction mixture is cooled
  11. concentrationconcentrated
  12. custompartitioned between EtOAc (500 mL) and saturated NaHCO3 solution (3×125 mL)
  13. dry with materialThe organic layer is dried (Na2SO4)
  14. concentrationconcentrated
  15. customThe crude product is purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-7ec1f533c6a34cfba0bef15b5ed2a2fc
Source dataset
uspto-grants-2009_05
Patent number
US07528160B2

Reaction notes

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