Water → (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole

HRID 852083Notes

Reaction equation

HRID 852083 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](O)[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S([O:30][CH2:31][C@@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1.O>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:30][CH2:31][C@H:32]4[CH2:33][O:34]4)=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 154187Glycidyl tosylate, (R)-HCID 179062783-(6-Fluoro-benzo[d]isoxazol-3-yl)-phenol

Product 1

HCID 58928269(R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazoleYield 78%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent4×

Procedure

To a cold (0° C.) solution of sodium hydride (1.80 g, 45.0 mmol) in dimethylformamide (anhydrous,40 mL) and under a nitrogen atmosphere, add dropwise a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (anhydrous, 50 mL). Precipitate forms. Cool (0° C.) reaction mixture for 20 minutes and the material solidifies. Add dimethylformamide (anhydrous, 120 mL) and (2R)-(−)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), dropwise, over a period of time of 0.5 hours, while cooling with an ice bath. After this addition, the reaction mixture becomes homogeneous. Warm reaction mixture to room temperature and stir overnight. Pour reaction mixture into cold water (600 mL), stir for 1 hour under an ice bath, filter and wash the filter cake with water to obtain an off-white solid. Add dichloromethane (200 mL) to the off-white solid, wash with saturated sodium chloride and dry (MgSO4). Directly purify by column (silica) chromatography (dichloromethane) and triturate with pentane to give the title compound as an off-white solid (9.70 g, 78% Yield). MS shows [M+H]+=286. NMR and microanalysis (C, H, N) are consistent with the final, desired compound. mp=132-133° C.

Workup

  1. temperatureCool
  2. custom(0° C.) reaction mixture for 20 minutes
  3. temperaturewhile cooling with an ice bath
  4. additionAfter this addition
  5. temperatureWarm
  6. customreaction mixture to room temperature
  7. additionPour
  8. stirringstir for 1 hour under an ice bath
  9. filtrationfilter
  10. washwash the filter cake with water
  11. customto obtain an off-white solid
  12. washAdd dichloromethane (200 mL) to the off-white solid, wash with saturated sodium chloride
  13. dry with materialdry (MgSO4)
  14. customDirectly purify by column (silica) chromatography (dichloromethane)
  15. customtriturate with pentane

Sources & evidence

ORD record
ord-5df833128839469bb15ed26757b92097
Source dataset
uspto-grants-2007_08
Patent number
US07253165B2

Reaction notes

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