反应详情

To a solution of benzyl(3R,4S)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (14.5 g, 47.6 mmol) in 116 mL of dehydrated tetrahydrofuran, 122 mL of a tetrahydrofuran solution of borane-tetrahydrofuran complex (1.17 mol/L, 143 mmol) was added dropwise over 20 minutes at an internal temperature of 40 to 44° C. The mixture was stirred at the same temperature for 7 hours. Subsequently, the reaction mixture was cooled to an internal temperature of 25° C. or below. At an internal temperature of 15 to 25° C., 14.5 mL of water was added dropwise and the mixture was stirred for 20 minutes. At an internal temperature of 10 to 18° C., 39.8 mL of triethylamine (286 mmol) was added dropwise and the mixture was stirred for 5 minutes. The mixture was then refluxed for 15 hours. Subsequently, the mixture was allowed to cool and concentrated under reduced pressure. To the resulting residue, 44 mL of water was added and the mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of water and extracted with 60 mL of 2 mol/L hydrochloric acid. The aqueous layer was cooled in a water bath under stirring and 60 mL of a 2 mol/L sodium hydroxide solution was added at an internal temperature of 20 to 28° C. to adjust the pH to about 12. This mixture was extracted with 102 mL of ethyl acetate. The organic layer was washed with 73 mL of 28% brine. To the organic layer, 20.2 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. Subsequently, the mixture was filtered through a cotton plug and washed with 22 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The product was dried at room temperature under reduced pressure for 1 hour to give 14.3 g of a crude product of the title compound as a pale yellow oil. This product was used in the subsequent step without further purification.

1. temperatureSubsequently, the reaction mixture was cooled to an internal temperature of 25° C. or below
2. stirringthe mixture was stirred for 20 minutes
3. stirringthe mixture was stirred for 5 minutes
4. temperatureThe mixture was then refluxed for 15 hours
5. temperatureto cool
6. concentrationconcentrated under reduced pressure
7. additionTo the resulting residue, 44 mL of water was added
8. extractionthe mixture was extracted with 102 mL of ethyl acetate
9. washThe organic layer was washed with 73 mL of water
10. extractionextracted with 60 mL of 2 mol/L hydrochloric acid
11. temperatureThe aqueous layer was cooled in a water bath
12. stirringunder stirring
13. addition60 mL of a 2 mol/L sodium hydroxide solution was added at an internal temperature of 20 to 28° C.
14. extractionThis mixture was extracted with 102 mL of ethyl acetate
15. washThe organic layer was washed with 73 mL of 28% brine
16. additionTo the organic layer, 20.2 g of anhydrous sodium sulfate was added
17. stirringthe mixture was stirred for 1 hour
18. filtrationSubsequently, the mixture was filtered through a cotton plug
19. washwashed with 22 mL of ethyl acetate
20. concentrationconcentrated under reduced pressure
21. customThe product was dried at room temperature under reduced pressure for 1 hour