Hydrochloric Acid → (1R,2S,4R)-5,5-Difluorobicyclo[2.2.1]heptan-2-amine hydrochloride

Temperature

60 °C

To a suspension of 2-((1R,2S,4R)-5,5-difluorobicyclo[2.2.1]-heptan-2-yl)isoindoline-1,3-dione (0.58 g, 2.09 mmol) in ethanol (anhydrous, 30 mL) was added hydrazine (0.10 mL, 3.14 mmol). After refluxing this mixture under nitrogen for 5 h, it was cooled in an ice bath, and hydrochloric acid (37%, 0.50 mL) was added. After stirring at 60° C. for 1.5 h, the mixture was cooled to ambient temperature. After the white solid was removed by filtration, the filter cake was washed with methanol, and the filtrate was conc. in vacuo. The resulting residue was diluted in ˜50 mL of water, filtered, and the filtrate was washed with diethyl ether (30 mL×3). The filtrate was then treated with sodium carbonate monohydrate to saturation, and the aqueous layer was extracted with diethyl ether (50 mL×3). These organic layers were combined, dried over potassium carbonate (solid), and filtered. The solution was treated with hydrochloric acid (1M aqueous, 4 mL), stirred for 5 min, and then concentrated in vacuo to give the title compound as a white solid.

1. temperatureAfter refluxing this mixture under nitrogen for 5 h
2. temperatureit was cooled in an ice bath
3. temperaturethe mixture was cooled to ambient temperature
4. customAfter the white solid was removed by filtration
5. washthe filter cake was washed with methanol
6. additionThe resulting residue was diluted in ˜50 mL of water
7. filtrationfiltered
8. washthe filtrate was washed with diethyl ether (30 mL×3)
9. additionThe filtrate was then treated with sodium carbonate monohydrate to saturation
10. extractionthe aqueous layer was extracted with diethyl ether (50 mL×3)
11. dry with materialdried over potassium carbonate (solid)
12. filtrationfiltered
13. additionThe solution was treated with hydrochloric acid (1M aqueous, 4 mL)
14. stirringstirred for 5 min
15. concentrationconcentrated in vacuo

ORD record

ord-71bc4525892b43d4ae7a757c1a8f3f51

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08686011B2