Sodium Hydroxide → HCID 69281970, compound

Temperature

0 °C

A solution of tert-butyl carbamate (4.18 g, 35.0 mmol) in propanol (39 ml) was sequentially treated with sodium hydroxide (1.376 g, 34.4 mmol) in water (72 ml) and tert-butyl hypochlorite (3.88 ml, 34.4 mmol). After 5 min of stirring, the reaction mixture was cooled to 0° C. A solution of (DHQD)2PHAL (0.555 g, 0.677 mmol) in propanol (39 ml), a solution of (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (3.34 g, 11.28 mmol) in propanol (68 ml), and potassium osmate dihydrate (0.166 g, 0.451 mmol) were sequentially added. The reaction mixture was stirred for three additional hours at 0° C., warmed to ambient temperature and after an additional 16 hours the light yellow homogenous solution was quenched with saturated aqueous sodium sulfite (100 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous magnesium sulfate and concentrated to afford a residue which was purified via column chromatography (25% to 40% EtOAc/Hex) to provide tert-butyl (1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (2.2991 g, 5.09 mmol, 45.1% yield) as an optically enriched mixture of enantiomers. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.52 (d, J=9.5 Hz, 1H), 7.25 (br. s., 1H), 7.10 (t, J=5.6 Hz, 2H), 5.89 (d, J=4.9 Hz, 1H), 5.03 (t, J=5.0 Hz, 1H), 4.83 (dd, J=8.9, 5.2 Hz, 1H), 1.40-1.34 (m, 9H), MS Anal. Calcd. for [M+H]+ C18H20BrF2N2O3: 429.1. found 431.3.

1. stirringThe reaction mixture was stirred for three additional hours at 0° C.
2. temperaturewarmed to ambient temperature and after an additional 16 hours the light yellow homogenous solution
3. customwas quenched with saturated aqueous sodium sulfite (100 mL)
4. extractionThe aqueous phase was extracted with ethyl acetate (2×50 mL)
5. washthe combined organic phases were washed with brine (100 mL)
6. dry with materialdried over anhydrous magnesium sulfate
7. concentrationconcentrated
8. customto afford a residue which
9. customwas purified via column chromatography (25% to 40% EtOAc/Hex)

ORD record

ord-e31af9e4a511499baac4927a3adea3d2

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08691821B2