Benzyl 6-oxa-3-azabicyclo(3.1.0)hexane-3-carboxylate → (3S,4R)-benzyl 3-ethyl-4-hydroxypyrrolidine-1-carboxylate

Temperature

-30 °C

A mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (4 g, 18.25 mmol) and bromo(dimethylsulfide) copper(I) (3.75 g, 18.25 mmol) in tetrahydrofuran (40 ml) was cooled to −30° C. A 3M solution of ethylmagnesium bromide (15.20 ml, 45.6 mmol) in Et2O was added dropwise to the reaction mixture over 35 minutes, maintaining an internal temperature of at or below −30° C. After the addition was complete, the resulting reaction mixture was allowed to warm to −15° C. over 45 minutes. At this time, the reaction was checked by HPLC. The reaction mixture was allowed to gradually warm up to rt and HPLC indicated that the reaction was complete. The reaction mixture was diluted with EtOAc (50 mL). The reaction mixture was then cooled in an ice bath and was quenched by slow addition of sat′d aq. ammonium chloride (˜10 mL). The organic layer was separated and was washed with H2O (20 ml). The organic layer was concentrated and the crude was purified by silica gel chromatography to give (3S,4R)-benzyl 3-ethyl-4-hydroxypyrrolidine-1-carboxylate (17.25 g, 69.2 mmol, 69.0% yield). LCMS: (M+23)=242, t=1.87 min.

1. temperaturemaintaining an internal temperature of at or below −30° C
2. additionAfter the addition
3. customthe resulting reaction mixture
4. temperatureto warm to −15° C. over 45 minutes
5. temperatureto gradually warm up to rt
6. temperatureThe reaction mixture was then cooled in an ice bath
7. customwas quenched by slow addition of sat′d aq. ammonium chloride (˜10 mL)
8. customThe organic layer was separated
9. washwas washed with H2O (20 ml)
10. concentrationThe organic layer was concentrated
11. customthe crude was purified by silica gel chromatography

ORD record

ord-4a94331a2b924e68ba80bb31f2ab2bd4

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09428511B2