Cyclohexane → 498532-06-2

To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.

1. waitThe stirring was continued at 0° C. for 10 min.
2. waitAfter 20 min
3. customthe reaction
4. customas quenched with 2 N HCl/Et2O (20 mL/40 mL)
5. customLayers were separated
6. extractionthe aqueous layer was extracted with ether (3×50 mL)
7. washCombined ether solution was washed with H2O (50 mL), brine (50 mL)
8. dry with materialdried with Na2SO4
9. customAfter removal of the solvent under reduced pressure
10. customthe resultant oily material was purified
11. customby flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc)

ORD record

ord-13fa80253a654d09bde9eed0b16e2dec

Source dataset

uspto-grants-2004_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06677462B2