Imidazole → (S)-tert-butyl 2-(2-cyanopyrrolidin-1-yl)-2-oxoethylcarbamate

Temperature

-35 °C

In a dry three-neck flask under a nitrogen atmosphere, 286 mL of pyridine, [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (13.5 g, 49.8 mmol) and imidazole (7.11 g, 104.6 mmol) were added successively. The reaction system was cooled down to −35° C., and phosphorus oxychloride (19 mL, 204.2 mmol) was then added dropwise to the solution with stirring. After stirring for 1 hour at −35° C., the reaction mixture was allowed to increase to room temperature, and stirred for another 0.5 hour. Pyridine was evaporated under low temperature, and the reaction mixture was diluted with water, then extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound [2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1e (10.7 g, yield 84.9%) as a white powder.

1. stirringAfter stirring for 1 hour at −35° C.
2. temperatureto increase to room temperature
3. stirringstirred for another 0.5 hour
4. customPyridine was evaporated under low temperature
5. additionthe reaction mixture was diluted with water
6. extractionextracted with ethyl acetate (200 mL×3)
7. washThe combined organic extracts were washed with 50 mL of saturated brine
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customThe residue was purified by silica gel column chromatography

ORD record

ord-72872afd737e4ff2a9075eb0e584a6d0

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08178575B2