Hydrogen Peroxide → HCID 86730048, compound

A mixture of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (2A, 2.1 g, 5.94 mmol) in DCM (10 ml) was added dropwise to a solution of ((1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane in DCM (30 ml) at −35° C. under nitrogen. (The borane reagent was made as following: To a mixture of S-Alpine-Boramine (8.4 g, 20.18 mmol) in THF (35 ml) was added BF3 ethereate (5.11 ml, 40.4 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 h, filtered under nitrogen, and the cake was washed with cold THF (2×6 ml). The filtrate and washes were combined and concentrated under vacuum. To the residue was added DCM (20 ml) and the solution was concentrated again. The reagent obtained was redissolved in DCM (30 ml) and used directly for the hydroboration step). After stirring at −35° C. to −30° C. for 4 h and at −25° C. to −20° C. for 2 h, MeOH (3.6 mL) was added and the reaction mixture was stirred at −10° C. for 10 min and at 0° C. for 10 min. The mixture was diluted with THF (25 ml), then a solution of NaOH (6N, 9.9 ml, 59.4 mmol) was added dropwise followed by H2O2 (30%, 6.07 ml, 59.4 mmol) and the mixture was stirred at room temperature for 16 h. To the mixture was added DCM (100 ml) and water (50 ml). The whole solution was filtered through a pad of CELITE® and the cake was washed with DCM. The two layers were separated, the aqueous layer was extracted with DCM (50 ml) which was combined with the organic layer. The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-50% EtOAc over 55 minutes) to afford 1.9 g (86%) of (5R,7S)-7-(6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one in a 8:1 ratio of two isomers. The mixture was carried into the next step without separating the diastereomers.

1. filtrationfiltered under nitrogen
2. washthe cake was washed with cold THF (2×6 ml)
3. concentrationconcentrated under vacuum
4. additionTo the residue was added DCM (20 ml)
5. concentrationthe solution was concentrated again
6. customThe reagent obtained
7. stirringAfter stirring at −35° C. to −30° C. for 4 h and at −25° C. to −20° C. for 2 h
8. stirringthe reaction mixture was stirred at −10° C. for 10 min and at 0° C. for 10 min
9. stirringthe mixture was stirred at room temperature for 16 h
10. filtrationThe whole solution was filtered through a pad of CELITE®
11. washthe cake was washed with DCM
12. customThe two layers were separated
13. extractionthe aqueous layer was extracted with DCM (50 ml) which
14. washThe combined organic layers were washed with water (100 ml) and brine (100 ml)
15. dry with materialdried over anhydrous Na2SO4
16. concentrationconcentrated in vacuo
17. customThe crude material was purified on a silica gel cartridge (40 g)
18. customan EtOAc/hexane gradient (0-50% EtOAc over 55 minutes)

ORD record

ord-76012dc142b34f00a2da9c28849e72ed

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09359286B2