反应详情

Under stirring by means of an impeller, O-tert-butyl-N,N′-diisopropylurea (3,020 g, 15.00 mol) was added at room temperature to a suspension of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (1,165 g, 4.994 mol) in dichloromethane (10 L). After rising in internal temperature and initiation of reflux had been observed, the mixture was cooled in an ice-water bath. The reaction mixture was cooled to room temperature. Thereafter, the ice-water bath was removed, and the reaction mixture was stirred for 1 hour, and subsequently, for 3 hours under heating at 40° C. The reaction mixture was further stirred for 1 hour with cooling in an ice-water bath, and insoluble material was removed through filtration. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified through silica gel column chromatography (silica gel: 4 kg, eluent; hexane:ethyl acetate=3:1), to thereby yield the title compound as pale yellow syrup (3-position isomer mixtures) (925.2 g, 64%). The diastereomers in terms of the 3-position of pyrrolidine can be easily separable. However, since the subsequent step include reaction involving epimerization, the diastereomers were used without performing purification. 1H-NMR spectral data of each diastereomer, which had been separately isolated, are given below.

1. temperatureof reflux
2. temperaturethe mixture was cooled in an ice-water bath
3. customThereafter, the ice-water bath was removed
4. temperaturesubsequently, for 3 hours under heating at 40° C
5. stirringThe reaction mixture was further stirred for 1 hour
6. temperaturewith cooling in an ice-water bath
7. custominsoluble material was removed through filtration
8. customThe filtrate was evaporated to dryness under reduced pressure
9. customthe residue was purified through silica gel column chromatography (silica gel: 4 kg, eluent; hexane:ethyl acetate=3:1)