Sodium hydride → (S)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole

HRID 852081Notes

Reaction equation

HRID 852081 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:31][C@@H:32]4[CH2:33][O:34]4)[CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 153296Oxiranemethanol, 4-methylbenzenesulfonate, (S)-HCID 179062783-(6-Fluoro-benzo[d]isoxazol-3-yl)-phenol

Product 1

HCID 58928256(S)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazoleYield 81%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

To a cold (0° C.) solution of sodium hydride (1.83 g, 45.79 mmol) in dimethylformamide (120 mL) and under a nitrogen atmosphere, add a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (50 mL) and stir for 1 hour. Add, dropwise, (2S)-(+)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), over a period of time of 0.5 hours. Let reaction mixture warm to room temperature and stir for 2 days. Quench with water, concentrate and add ethyl acetate/water. Wash with water, saturated sodium chloride and dry (MgSO4) to give the crude compound. Purify by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (10.07 g, 81% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 18.14 minutes [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 88.3% e.e. mp=83-84° C.

Workup

  1. additionAdd
  2. customreaction mixture
  3. stirringstir for 2 days
  4. customQuench with water
  5. concentrationconcentrate
  6. additionadd ethyl acetate/water
  7. washWash with water, saturated sodium chloride
  8. dry with materialdry (MgSO4)
  9. customto give the crude compound
  10. customPurify by column (silica) chromatography
  11. washeluting with a graded solvent mixtures of toluene to 1% ether in toluene

Sources & evidence

ORD record
ord-e4201509bebe4a84aeb9813217b4a3bc
Source dataset
uspto-grants-2007_08
Patent number
US07253165B2

Reaction notes

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