4-Methylmorpholine → (3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol

HRID 1506299Notes

Reaction equation

HRID 1506299 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](O)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 583740941236188-80-9

Product 1

HCID 66955108(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanolYield 46.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 1 g, 3.89 mmol) in THF (10 mL), cooled to −10° C., was added N-methylmorpholine (0.470 mL, 4.28 mmol) followed by isobutyl chloroformate (0.562 mL, 4.28 mmol) over a period of 3 min. After 15 min. at −10° C., this heterogeneous reaction mixture was added to a suspension of sodium borohydride (0.191 g, 5.06 mmol) in THF (12 mL) and methanol (3.0 mL) at −78° C. over a period of 10 min. using a Pasteur pipette. The reaction mixture was stirred at −78° C. for 10 min. The reaction mixture was allowed to warm to −20° C. over a period of 30 min. and quenched by the slow addition of AcOH in water (1:9 mL). The reaction mixture was allowed to come to room temperature, concentrated under reduced pressure and the residue partitioned between ethyl acetate (60 mL) and water (10 mL). The ethyl acetate layer was separated and washed sequentially with sat. aq. sodium bicarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was subjected to silica gel column chromatography using hexane/ethyl acetate to yield (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (0.44 g, 1.809 mmol, 46.5% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H); LCMS M+1=244.

Workup

  1. temperatureto warm to −20° C. over a period of 30 min.
  2. customquenched by the slow addition of AcOH in water (1:9 mL)
  3. customto come to room temperature
  4. concentrationconcentrated under reduced pressure
  5. customthe residue partitioned between ethyl acetate (60 mL) and water (10 mL)
  6. customThe ethyl acetate layer was separated
  7. washwashed sequentially with sat. aq. sodium bicarbonate (10 mL), brine (10 mL)
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-68e19f360c2243778d48294bed33d103
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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