Ethyl Acetate → 5-Fluoro-3-(4-methoxybutyl)-3-(2-(methylamino)ethyl)isobenzofuran-1(3h)-one

Temperatur

-30 °C

To a solution of tert-butyl 3-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-fluorophenyl)-3-oxopropyl(methyl)carbamate (153 mg, 0.4 mmol) in dry toluene (2 mL) at −30° C. was added 4-methoxybutylmagnesium chloride (2.0 M, 0.6 mL, 1.2 mmol, prepared by refluxing 4-methoxybutylchloride and magnesium in THF for 4 h). The reaction was stirred at −30° C. for 2 h. After warming to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and brine, separated. The aqueous phase was extracted with ethyl acetate once. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g column, EtOAc/Hexanes) to give the Grignard-addition adduct (130 mg, 70%). A portion of the adduct (30 mg, 0.064 mmol) was dissolved in acetonitrile (4 mL), put in a seal tube and added concentrated sulfuric acid (3 drops). The tube was then sealed and heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was purified by preparative HPLC (C-18 column, 2 to 60% CH3CN in H2O containing 0.01% CF3CO2H over 20 min, 20 mL min−1) to afford product as TFA salt (17 mg, 65%).

1. temperatureAfter warming to room temperature
2. customseparated
3. extractionThe aqueous phase was extracted with ethyl acetate once
4. dry with materialThe combined organic phases were dried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. customThe residue was purified by column chromatography on silica gel (40 g column, EtOAc/Hexanes)

ORD-Eintrag

ord-69d215840c564c61963362d88317e549

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08106221B2