Ammonia → 2-Methyl-2-propanyl (2S,4S)-2-carbamoyl-4-fluoro-1-pyrrolidinecarboxylate

Temperature

-11 °C

(2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (70.0 g) was dissolved in tetrahydrofuran (700 mL) and then cooled to −11° C. To this solution, triethylamine (33.4 g) and ethyl chlorocarbonate (35.8 g) were slowly added and stirred at −15° C. for 30 minutes. Subsequently, 28% aqueous ammonia (73 mL) was added to the reaction mixture. After stirring at −10° C. for 40 minutes, a mixture of ethyl acetate and tetrahydrofuran (4:1, 1400 mL) and water (230 mL) were added and stirred. The reaction mixture was separated into organic and aqueous layers, and the aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL). The combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether to give the titled compound (57.7 g, white powder).

1. stirringAfter stirring at −10° C. for 40 minutes
2. additionwere added
3. stirringstirred
4. customThe reaction mixture was separated into organic and aqueous layers
5. extractionthe aqueous layer was further extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1, 350 mL)
6. washThe combined organic layers were washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride
7. dry with materialdried over anhydrous sodium sulfate
8. concentrationconcentrated under reduced pressure
9. customThe resulting crude crystal was recrystallized from a mixed solvent of acetonitrile and diisopropyl ether

ORD record

ord-8bf134063167430ab346870b4c761938

Source dataset

uspto-grants-2007_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07279584B2