Benzene, 1-fluoro-2-(trifluoromethyl)- → 4-(2-Fluoro-3-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester

Temperature

-78 °C

To a stirred solution of 2-fluorobenzotrifluoride (19.4 g, 118 mmol) and anhydrous THF (300 mL) at −78° C. under nitrogen was added was added LDA (65.0 mL of a 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 130 mmol) dropwise over 25 min. After 165 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (40.1 g, 147 mmol) in anhydrous THF (100 mL) was added dropwise over 50 min and the reaction stirred at −78° C. for 20 min and at room temperature for 85 min. The reaction was quenched with saturated ammonium chloride (40 mL) and the mixture concentrated. The residue was taken up in ethyl acetate (400 mL) and washed successively with 1 N HCl (200 mL), 5% aqueous potassium carbonate, water (200 mL), and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give an amber oil. The product was chromatographed on silica gel (300 g), using a step gradient elution of 20% ethyl acetate/heptane to 60% ethyl acetate/heptane, to afford 23.2 g (52%) of the desired product as an off-white solid.

1. customThe reaction was quenched with saturated ammonium chloride (40 mL)
2. concentrationthe mixture concentrated
3. washwashed successively with 1 N HCl (200 mL), 5% aqueous potassium carbonate, water (200 mL), and brine (200 mL)
4. dry with materialThe organic phase was dried over magnesium sulfate
5. filtrationfiltered
6. customthe solvent removed
7. customto give an amber oil
8. customThe product was chromatographed on silica gel (300 g)
9. washa step gradient elution of 20% ethyl acetate/heptane to 60% ethyl acetate/heptane

ORD record

ord-0b5b24ce55f245ab8f8190f3cdce8152

Source dataset

uspto-grants-2010_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07772252B2