Potassium Carbonate → Ethyl 4-oxobutanoate

A mixture of 4-[4-(3-chloropropoxy)-3,5-difluorophenyl]-4-oxo-butyric acid ethyl ester (5 g, 14.9 mmol), K2CO3 (7.2 g, 52.1 mmol), NaI (220 mg, 1.4 mmol), and Benzenesulfonate; (R)-methylpyrrolidinium (8 g, 33 mmol) in CH3CN (110 mL) was heated under argon at 80° C. for 36 h. The reaction was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material (96% purity). The crude material was purified by ISCO (80 g silica gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 0.1% ammonium hydroxide in methylene chloride. The isolated material was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The isolated material was crystallized with a mixture of methylene chloride, ether and hexane to obtain 4-{3,5-difluoro-4-[3-(R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (3.97 g, 70%, 99% purity), MS m/z=384 (M+H).

1. concentrationThe reaction was concentrated
2. custompartitioned between saturated aqueous sodium bicarbonate solution and methylene chloride
3. extractionThe aqueous layer was extracted twice with methylene chloride
4. washthe combined organics was washed with brine
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. customto provide a crude material (96% purity)
9. customThe crude material was purified by ISCO (80 g silica gel column) chromatography
10. dissolutionThe isolated material was dissolved in methylene chloride
11. washwashed with saturated aqueous sodium bicarbonate solution, brine
12. dry with materialdried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. customThe isolated material was crystallized with a mixture of methylene chloride, ether and hexane

ORD-Eintrag

ord-51691f3b3d324b0ca16459278fb1898c

Quelldatensatz

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08207168B2