Citric Acid → (1S,4S)-5-(1-(4-chlorophenyl)cyclopropanecarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptan-3-one

1-(4-chlorophenyl)cyclopropanecarboxylic acid (8.58 g) and dimethylformamide (136 mg) were suspended in toluene (20 mL). The mixture was cooled down to room temperature then a solution of oxalyl chloride (5.25 g) in toluene (6.7 mL) was dropped within 10 min. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. At 0-5° C., (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-3-one methanesulfonate (CAS #: 769167-53-5; 8 g) and tetrahydrofuran (13.2 mL) were added to the reaction mixture, followed by a dropwise addition of triethylamine (14.5 g). The mixture was stirred at 22° C. for 16 hr. An aqueous solution of citric acid (10%, 30 mL) was added and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was crystallized in a mixture of dichloromethane, ethyl acetate and heptane to yield 10.6 g (95%) of the title compound as a white solid. MS (ESI): m/z=292.07 [M+H]+.

1. stirringThe mixture was stirred at 22° C. for 16 hr
2. customthe phases were separated
3. extractionThe aqueous layer was extracted with ethyl acetate
4. washThe combined organic layers were washed with brine (20 mL)
5. dry with materialdried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe crude mixture was crystallized in a mixture of dichloromethane, ethyl acetate and heptane

ORD record

ord-25c1674588bc447fa089d81ca5a1c416

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08163793B2