Imidazole → tert-Butyl (2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylate

Temperature

2.5 °C

In a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer and reflux condenser, pyridine (1000 ml) and imidazole (58.6 gm, 0.86 mol) were added at 25-35° C. while stirring. The reaction mixture was cooled to 0-5° C. while stirring for 30 min, tert-butyl 2-(aminocarbonyl)-4-fluoropyrrolidine-1-carboxylate (100 gm, 0.43 mol) and phosphorous oxychloride (165.7 gm, 1.07 mol) were added slowly at 0-5° C. while stirring. After addition, the reaction mixture was maintained for 1 hr. The progress of the reaction was monitored by TLC. After ascertaining completion of the reaction by TLC, the reaction mixture was poured into an ice cold water (5 L), sodium chloride and ethylacetate (800 ml) mixture. The aqueous layer was washed with an ethyl acetate (800 ml), dilute HCl (4 100), sodium bicarbonate and saturated brine solution. The ethylacetate layer was distilled below 55° C. under vacuum and hexane (500 ml) was added to the resulting mass. Trace ethylacetate was distilled off. The resulting mass was taken as such to the next stage.

1. customIn a 5.0 L 4-necked RB flask, fitted with a mechanical stirrer
2. temperaturereflux condenser
3. stirringwhile stirring for 30 min
4. stirringwhile stirring
5. additionAfter addition
6. temperaturethe reaction mixture was maintained for 1 hr
7. customcompletion of the reaction by TLC
8. washThe aqueous layer was washed with an ethyl acetate (800 ml), dilute HCl (4 100), sodium bicarbonate and saturated brine solution
9. distillationThe ethylacetate layer was distilled below 55° C. under vacuum and hexane (500 ml)
10. additionwas added to the resulting mass
11. distillationTrace ethylacetate was distilled off

ORD record

ord-0e09863d8d584b99a237c15fc84ea1f2

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07893103B2