4-Methylmorpholine → HCID 67168678, compound

Temperature

0 °C

To a solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate 1-5D, 3.0 g, 11.7 mmol) in THF (20 mL) at 0° C. was added N-methylmorpholine (1.92 mL, 17.5 mmol) followed by isobutyl chloroformate (2.30 mL, 17.5 mmol) via syringe over 5 min. The resulting suspension was stirred at 0° C. for 15 min. The suspension was then added to a suspension of sodium borohydride (0.794 g, 21.0 mmol) in THF (40 mL) and methanol (12 mL) at −78° C. via a 10 mL syringe. During the addition, frothing was observed. The reaction mixture was stirred for 60 min. The reaction mixture was slowly warmed to approximately −20° C. and quenched with a 20 mL of a 1:9 mixture of acetic acid in water. The reaction mixture was then stirred at room temperature for 60 min. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (120 mL), washed with water (20 mL), saturated aqueous solution of sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layer was collected, the aqueous layers were back-extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1% to load; 5%-9%-12%) afforded (5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)methanol (1.79 g, 7.36 mmol, 63% yield) as a clear, colorless oil. The compound had an HPLC ret. time=2.02 min. (condition A); LC/MS M+1=243.8.

1. additionDuring the addition, frothing
2. stirringThe reaction mixture was stirred for 60 min
3. temperatureThe reaction mixture was slowly warmed to approximately −20° C.
4. customquenched with a 20 mL of a 1:9 mixture of acetic acid in water
5. stirringThe reaction mixture was then stirred at room temperature for 60 min
6. customThe solvent was removed under reduced pressure
7. additionthe residue was diluted with ethyl acetate (120 mL)
8. washwashed with water (20 mL), saturated aqueous solution of sodium bicarbonate (2×20 mL) and brine (20 mL)
9. customThe organic layer was collected
10. extractionthe aqueous layers were back-extracted with ethyl acetate (100 mL)
11. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
12. concentrationConcentration under reduced pressure
13. customfollowed by purification by flash silica gel chromatography
14. additiona mixture of ethyl acetate in hexane (1% to load; 5%-9%-12%)

ORD record

ord-e48af8c6e8ac417c8ebdb66f88d5abcd

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216972B2