Tetrahydrofuran → 2-(5-Bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol

To a flask containing 3-acetyl-5-bromopyridine (2.27 g, 11.4 mmol) was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) at 0° C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added, and the reaction stirred at room temperature until the reaction was complete. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (10-50% ethyl acetate in hexanes) to provide the racemic title compound: LCMS m/z 269.85 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 8.70 (s, 1H), 8.65 (1H), 8.13 (s, 1H), 1.81 (s, 3H). The racemic title compound was resolved by supercritical fluid chromatography on a chiral AD column, eluting with 10% ethanol:CO2. Data for enantiomer A: LCMS m/z 271.85 [M+H]+; 1H NMR (500 MHz, CDCl3) 8.71 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 1.82 (s, 3H). Data for enantiomer B: LCMS m/z 271.83 [M+H]+; 1H NMR (500 MHz, CDCl3) 8.71 (s, 1H), 8.68 (s, 1H), 8.10 (s, 1H), 1.81 (s, 3H).

1. concentrationThe reaction was then concentrated under reduced pressure
2. additiondiluted with ethyl acetate
3. washwashed with water and saturated aqueous sodium bicarbonate solution
4. customThe organic layer was separated
5. dry with materialdried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customto give a residue that
9. customwas purified by flash chromatography on silica gel (10-50% ethyl acetate in hexanes)

ORD record

ord-c76ad44f83c14e89ac5d55cc3d6d35a8

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09173873B2