Hydrochloric Acid → Diethyl 2-(2,2,2-trifluoro-1-(phenylamino)ethyl)malonate

A solution of diethyl malonate (1.98 mL, 13.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, over 20 min, into a dispersion of sodium hydride (60% in oil, 0.52 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) at 0° C., after which compound 325 (2.6 g, 11.9 mmol) was added and the mixture was stirred vigorously at reflux for 16 h. The reaction mixture was cooled, acidified to pH 3 using a 1N HCl solution. The aqueous layer was extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent dichloromethane-hexane, 0:100 to 60:40) to afford title compound 326 (2.16 g, 6.48 mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.21-7.16 (m, 2H), 6.81-6.76 (m, 1H), 6.75-6.71 (m, 2H), 5.06 (d, J=10.4 Hz, 1H), 4.83-4.73 (m, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.18-4.05 (m, 2H), 3.85 (d, J=4.4 Hz, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H). LRMS (M+1) 334.1 (100%).

1. temperatureat reflux for 16 h
2. temperatureThe reaction mixture was cooled
3. extractionThe aqueous layer was extracted twice with EtOAc
4. dry with materialdried over sodium sulfate
5. customthe solvents were removed under reduced pressure
6. customThe residue was purified by column chromatography on silica gel (eluent dichloromethane-hexane, 0:100 to 60:40)

ORD record

ord-77d4f0d2bd7f4e8899b13ddd4c140444

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093264B2