Carbon Dioxide → HCID 68632266, compound

n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added to a solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) in an argon atmosphere at −78° C. A colourless precipitate was formed. After 10 min the solution was heated to room temperature. Carbon dioxide was then introduced into the reaction mixture for approx. 3 min. A colourless solution was formed. After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ≦30° C.). The colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to −78° C. and tert-butyl lithium (8.39 mmol, 5.59 ml, 1.5M in pentane) was added in drops. An orange solution was formed. This was stirred for 1 h at −20° C. and then cooled to −78° C. 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexanone [1.97 g, 8.39 mmol, in absolute tetrahydrofuran (20 ml)] was then added in drops and the resulting solution stirred for 2 h. Saturated aqueous ammonium chloride solution (50 ml) was then added in drops to the reaction mixture, stirred for 10 min, the mixture heated to 0° C. and stirred for 20 min. 2N aqueous hydrogen chloride solution (50 ml) was added thereto and stirred for 10 min (light gas development). The pH value of the milky suspension was then basified with saturated sodium hydrogencarbonate solution (50 ml) and 5N sodium hydroxide solution (20 ml). After 10 min the phases were separated. The organic phase contained a colourless solid. The phases were separated. The aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml). The organic solutions were combined. The volatile constituents were completely removed in a vacuum. The remaining light brown powder was extracted with methanol (5×75 ml). The residue was exclusively composed of the non-polar diastereoisomer 6b/7b (450 mg, 1.23 mmol, 16%). The extracts were concentrated until dry in a vacuum. The residue was taken up in methanol (approx. 30 ml). A light-coloured solid did not dissolve. This was separated by means of a fritted glass filter and then dried in a vacuum. 980 mg (2.67 mmol, 35%) of a colourless powder were obtained. This was composed of the two diastereoisomers.

1. customA colourless precipitate was formed
2. customA colourless solution was formed
3. customAfter 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ≦30° C.)
4. dissolutionThe colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml)
5. temperatureThe light yellow reaction mixture was cooled to −78° C.
6. customAn orange solution was formed
7. temperaturecooled to −78° C
8. stirringthe resulting solution stirred for 2 h
9. stirringstirred for 10 min
10. temperaturethe mixture heated to 0° C.
11. stirringstirred for 20 min
12. stirringstirred for 10 min (light gas development)
13. customAfter 10 min the phases were separated
14. customThe phases were separated
15. extractionThe aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml)
16. customThe volatile constituents were completely removed in a vacuum
17. extractionThe remaining light brown powder was extracted with methanol (5×75 ml)
18. concentrationThe extracts were concentrated
19. customuntil dry in a vacuum
20. dissolutionA light-coloured solid did not dissolve
21. customThis was separated by means of a fritted glass
22. filtrationfilter
23. customdried in a vacuum

ORD record

ord-72e2f33092b147939beb1372a8755d91

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08835689B2