反应详情

A 20.53 g (56.96 mmol) portion of 4-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-2-pyrrolidone was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 60 ml of tetrahydrofuran, and to the resulting solution which was cooled in an ice bath and stirred was subsequently added 2.51 g (62.7 mmol) of 60% sodium hydride gradually. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, 7.21 ml (62.7 mmol) of benzyl chloride was added dropwise thereto, and the resulting reaction solution was stirred for 1 hour at the same temperature and then for 12 hours at room temperature. Water was added to the reaction solution which was cooled in an ice bath and stirred, and then separation of layers was effected by adding ethyl acetate. The thus separated organic layer was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 18.00 g (70.1%) of the title compound as a 1:1 diastereomer mixture. Thereafter, the thus obtained title compound was again subjected to a silica gel column chromatography to separate it into diastereoisomers A and B, and the following reaction was carried out using the Isomer B.

1. temperatureto the resulting solution which was cooled in an ice bath
2. stirringAfter 10 minutes of stirring
3. stirringthe reaction mixture was stirred at room temperature for 1 hour
4. temperatureWhile cooling in an ice bath
5. stirringwith stirring
6. customthe resulting reaction solution
7. stirringwas stirred for 1 hour at the same temperature
8. temperaturewas cooled in an ice bath
9. stirringstirred
10. customseparation of layers
11. additionby adding ethyl acetate
12. washThe thus separated organic layer was washed with saturated brine
13. extractionthe aqueous layer was extracted with ethyl acetate
14. dry with materialThe organic layer was dried over anhydrous sodium sulfate
15. filtrationAfter filtration
16. customthe solvent was evaporated under a reduced pressure
17. customthe resulting residue was purified by a silica gel column chromatography