Hydrochloric Acid → 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one

Temperature

10 °C

To a mixture of (1R,2R)-2-aminocyclohexanol hydrochloride (0.418 g, 2.76 mmol), nickel(II) chloride hexahydrate (0.328 g, 1.378 mmol) and 3,5-difluorophenylboronic acid (6.53 g, 41.3 mmol) was added NaHMDS in THF (55.1 mL, 55.1 mmol) at 10° C. dropwise under N2. After addition, the mixture was stirred at 10° C. for 20 min. 2-Propanol (113 mL) (previously bubbled by N2) was added at 0° C. and then the mixture was stirred at RT for 10 min. 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Preparation X1) (7.5 g, 27.6 mmol). in THF was added dropwise and the mixture was heated at 60° C. overnight. The reaction mixture was cooled in ice bath, added 1.0 HCl until acidic and stirred for 10 min. Concentrated in vacuum. Extracted with EtOAc and the organic layer was washed with brine and concentrated. The residue was purified by column chromatography on silica gel to give 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (1.6 g, 7.54 mmol, 27.4% yield). 1H NMR (500 MHz, CDCl3) δ ppm 6.78 (dd, J=8.24, 2.14 Hz, 2H) 6.62-6.75 (m, 1H) 4.21 (dd, J=11.44, 5.65 Hz, 2H) 3.85-4.01 (m, 2H) 3.76 (dd, J=8.55, 6.10 Hz, 1H) 2.60-2.75 (m, 1H) 2.48-2.60 (m, 1H)

1. additionAfter addition
2. custom2-Propanol (113 mL) (previously bubbled by N2)
3. additionwas added at 0° C.
4. stirringthe mixture was stirred at RT for 10 min
5. temperaturethe mixture was heated at 60° C. overnight
6. temperatureThe reaction mixture was cooled in ice bath
7. stirringstirred for 10 min
8. concentrationConcentrated in vacuum
9. extractionExtracted with EtOAc
10. washthe organic layer was washed with brine
11. concentrationconcentrated
12. customThe residue was purified by column chromatography on silica gel

ORD record

ord-72a88b956bf74a87af0dcc422106ec63

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08486952B2