p-Toluenesulfonic acid → 4-[3,5-Difluoro-4-(methylthio)phenyl]-5-methyl-3-phenylisoxazole

온도

-25 °C

To a solution of lithium diisopropylamide (82 mmol) in anhydrous THF (200 mL), cooled to −45° C., was added a solution of 2-[3,5-difluoro-4-(methylthio)-phenyl]-1-phenylethanone oxime (5.7 g, 19 mmol) in anhydrous THF (15 mL), controlling the reaction temperature between −40 and −50° C. The mixture was allowed to warm to −25±5° C., held there for 1 hour, and cooled to −55° C. Excess ethyl acetate (20 g, 220 mmol) was gradually added to the mixture, and the mixture allowed to warm to 10° C. Dilute ammonium chloride solution was added, and the mixture extracted with dichloromethane (1×500 mL, 2×100 mL). The combined extracts were washed with dilute ammonium chloride, dried using magnesium sulfate, and concentrated. The residue was dissolved in dichloromethane (100 mL). The P-toluenesulfonic acid (1.0 g, 6.4 mmol) was added, and the mixture heated and held at reflux for 1 hour. The cool mixture was washed with dilute sodium bicarbonate, and the aqueous wash extracted with dichloromethane. The combined organic phases were dried using magnesium sulfate, and concentrated. The product was isolated by silica gel chromatography using 5% ethyl acetate in hexanes to give 4-[3,5-difluoro-4-(methylthio)phenyl]-5-methyl-3-phenylisoxazole as a yellow solid (2.9 g, 47%). 1H NMR (CDCl3/400 MHz) 7.33-7.42 (m, 5H), 6.68-6.73 (m, 2H), 2.48 (s, 3H) 2.47 (s, 3H). HRMS m/z 318.0769 (M+H+, calcd 318.0764). Anal. Calcd for C17H13F2NOS: C, 64.34; H, 4.13; N, 4.41; Found: C, 64.22; H, 4.16, N 4.28.

1. customthe reaction temperature between −40 and −50° C
2. temperaturecooled to −55° C
3. temperatureto warm to 10° C
4. extractionthe mixture extracted with dichloromethane (1×500 mL, 2×100 mL)
5. washThe combined extracts were washed with dilute ammonium chloride
6. customdried
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in dichloromethane (100 mL)
9. temperaturethe mixture heated
10. temperatureat reflux for 1 hour
11. washThe cool mixture was washed with dilute sodium bicarbonate
12. washthe aqueous wash
13. extractionextracted with dichloromethane
14. customThe combined organic phases were dried
15. concentrationconcentrated
16. customThe product was isolated by silica gel chromatography

ORD 기록

ord-4d1d73775b52488f87037d00df6dcb42

출처 데이터셋

uspto-grants-2004_01

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US06673818B2