反应详情

Under stirring by means of an impeller, O-t-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), which had been produced through the method described in the literature (i.e., Culbertson T. P., Domagala J. M., Nichols J. F., Priebe S., and Skeean R. W., J. Med. Chem., 1987, 30, 1711-1715), in dichloromethane (10 L). After an increase in internal temperature and initiation of reflux had been confirmed, 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. Subsequently, the mixture was stirred for 3 hours under heating at 40° C. The reaction mixture was 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 readily fractionated. However, since the subsequent step include reaction involving epimerization, the diastereomers were used without performing fractionation. 1H-NMR spectral data of each diastereomer, which had been separately fractionated, are given below.

1. customhad been produced through the method
2. temperatureAfter an increase in internal temperature and initiation
3. temperatureof reflux
4. temperaturethe mixture was cooled in an ice-water bath
5. customThereafter, the ice-water bath was removed
6. stirringSubsequently, the mixture was stirred for 3 hours
7. temperatureunder heating at 40° C
8. stirringThe reaction mixture was stirred for 1 hour
9. temperaturewith cooling in an ice-water bath
10. custominsoluble material was removed through filtration
11. customThe filtrate was evaporated to dryness under reduced pressure
12. customthe residue was purified through silica gel column chromatography (silica gel: 4 kg, eluent: hexane:ethyl acetate=3:1)