Diisopropylamine → (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one

A solution of diisopropylamine (3.44 g) in tetrahydrofuran (50 mL) was ice-cooled under a nitrogen atmosphere and 1.6 mol/L n-butyllithium-hexane solution (20.8 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (3.28 mL) was added to the reaction solution, and the mixture was stirred at the same temperature for 30 min. A solution of tert-butyl [(1S)-1-methyl-2-oxopropyl]carbamate (4.48 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred at the same temperature for 5 hr, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (50 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (150 mL), and diisopropylethylamine (11.5 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→10%), and the obtained solid was recrystallized from isopropanol/hexane to give the title compound as colorless crystals (yield: 1.51 g, 55%).

1. temperaturecooled under a nitrogen atmosphere
2. addition1.6 mol/L n-butyllithium-hexane solution (20.8 mL) was added
3. stirringthe mixture was stirred at the same temperature for 30 min
4. stirringThe mixture was stirred at the same temperature for 5 hr
5. extractionthe mixture was extracted with ethyl acetate
6. washThe obtained organic layer was washed with saturated brine
7. dry with materialdried over anhydrous magnesium sulfate
8. concentrationconcentrated under reduced pressure
9. customThe residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%)
10. dissolutionthe obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (50 mL)
11. stirringthe mixture was stirred at room temperature for 2 hr
12. concentrationThe reaction solution was concentrated under reduced pressure
13. dissolutionthe residue was dissolved in tetrahydrofuran (150 mL)
14. additiondiisopropylethylamine (11.5 mL) was added
15. temperatureThe reaction solution was refluxed
16. temperatureunder heating for 4 hr
17. concentrationconcentrated under reduced pressure
18. customThe residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→10%)
19. customthe obtained solid was recrystallized from isopropanol/hexane

ORD record

ord-02861ae7732c46bc93f9ff14d850589e

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420694B2