Sulfuric Acid → HCID 19608698, Verbindung

Temperatur

-20 °C

1-(3-Fluoro-4-methoxyphenyl)-2-phenyl-ethan-1-one oxime from Step 2 (2.00 g, 7.71 mmol) and anhydrous THF (80 mL) under a nitrogen blanket was cooled to -20° C., and n-butyllithium (1.6N, 12.0 mL) was added, via syringe, over 20 minutes, keeping the reaction temperature <-10° C. The deep red suspension was stirred at -20° C. for 1 hour, warmed to room temperature, and stirred at room temperature for 1 hour. Succinic anhydride (926 mg, 9.26 mmol) was added in one portion, and the yellow reaction was stirred for 16 hours without temperature control. Sulfuric acid (conc., 2.1 mL) was added, and the reaction was warmed to reflux. After 2 hours, the brown mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ether (2×100 mL). The ethereal solution was extracted with dilute sodium hydroxide (2×100 mL), and the combined basic extracts were acidified to pH <2 with hydrochloric acid (conc.). The acidic aqueous phase was extracted with ether (2×100 mL). This ethereal solution was evaporated under reduced pressure to a residue. The residue was applied to a column of silica gel (200 cc) and eluted (10% methanol in dichloromethane) to yield, upon concentration of the appropriate fractions, a crude solid. The solid was recrystallized from hot ethanol and 0.1N HCl to yield, upon filtration and drying, [3-(3-fluoro-4-methoxyphenyl)-4-phenylisoxazol-5-yl]propanoic acid as ivory colored crystals (367 mg, 14%): mp 129°-131° C. (dec). Mass Spectrum: MH+=342. 1H NMR (CDCl3 /300 MHz) δ 7.39 (m, 3H), 7.22-7.12 (m, 4H), 6.87 (t, J=8.46 Hz, 1H), 3.88 (s, 3H), 3.09 (t, J=8.05 Hz, 2H), 2.80 (t, J=8.05 Hz, 2H). 19F NMR(CDCl3 /282.2 MHz) : -135.466 (m).

1. customthe reaction temperature <-10° C
2. temperaturewarmed to room temperature
3. stirringstirred at room temperature for 1 hour
4. customthe yellow reaction
5. stirringwas stirred for 16 hours without temperature control
6. temperaturethe reaction was warmed to reflux
7. waitAfter 2 hours
8. temperaturethe brown mixture was cooled to room temperature
9. extractionextracted with ether (2×100 mL)
10. extractionThe ethereal solution was extracted with dilute sodium hydroxide (2×100 mL)
11. extractionThe acidic aqueous phase was extracted with ether (2×100 mL)
12. customThis ethereal solution was evaporated under reduced pressure to a residue
13. washeluted (10% methanol in dichloromethane)
14. customto yield, upon concentration of the appropriate fractions
15. customThe solid was recrystallized from hot ethanol and 0.1N HCl
16. customto yield, upon filtration
17. customdrying

ORD-Eintrag

ord-899e1b0d730441849d06367f5063bb78

Quelldatensatz

uspto-grants-1999_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05859257