反应详情

To a suspension of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid produced by the method described in Culbertson T. P., Domagala J. M., Nichols J. F., Priebe S., and Skeean R. W., J. Med. Chem., 1987, 30, 1711-1715 (1165 g, 4.994 mol) in dichloromethane (10 L), O-tertiary butyl-N,N′-diisopropylurea (3020 g, 15.00 mol) was added at room temperature with stirring. When increase in the inner temperature and starting of refluxing were noted, the reaction system was cooled in an ice bath. After cooling the reaction mixture to room temperature, the mixture was stirred for 1 hour after removing the ice bath, and for another 3 hours while heating to 40° C. After stirring the reaction mixture for another 1 hour with cooling in an ice bath, the insoluble content was removed, and the filtrate was dried under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 4 kg; elusion by hexane:ethyl acetate, 3:1) to obtain 925.2 g (64%) of the title compound (a mixture of isomers at position 3) as a pale yellow syrup. Although separation of the diastereomers of position 3 of the pyrrolidine was easy, the diastereomers were used without separation since the subsequent step involved epimerization. 1H-NMR spectrum of the isomers aliquoted for evaluation purpose are shown below.

1. customproduced by the method
2. temperatureWhen increase in the inner temperature
3. temperatureof refluxing
4. temperaturethe reaction system was cooled in an ice bath
5. stirringthe mixture was stirred for 1 hour
6. customafter removing the ice bath
7. temperaturefor another 3 hours while heating to 40° C
8. stirringAfter stirring the reaction mixture for another 1 hour
9. temperaturewith cooling in an ice bath
10. customthe insoluble content was removed
11. customthe filtrate was dried under reduced pressure
12. customThe residue was purified by silica gel column chromatography (silica gel: 4 kg; elusion by hexane:ethyl acetate, 3:1)