反应详情

温度

0 °C

Under a nitrogen stream, quinidine (69.9 g, 0.215 mol) and tetrahydrofuran (200 mL) were charged and the mixture was cooled to −5 to 5° C. tert-Butyl 2,4-dioxo-3-oxa-7-azabicyclo[3,3,1]nonane-7-carboxylate (50.0 g, 0.196 mol) was added at the same temperature, and the used container was washed with tetrahydrofuran (50.0 mL). Methanol (9.41 g, 0.29 4 mol) was added dropwise at −5 to 5° C., and the mixture was stirred at −5 to 5° C. for 2 hr. To the reaction mixture were added ethyl acetate (350 mL) and 20 w/v % aqueous citric acid solution (250 mL), and the mixture was partitioned. The aqueous layer was extracted again with ethyl acetate (125 mL×2). The organic layers were combined and washed successively with 20 w/v % aqueous citric acid solution (250 mL) and water (250 mL×2). The organic layer was concentrated under reduced pressure. To the residue were added ethanol (100 mL) and ethyl acetate (450 mL), the mixture was heated to 60-70° C., and (R)-phenethylamine (23.7 g, 0.196 mol) was added. The mixture was stirred at 50-60° C. for 1 hr, at 20-30° C. for 1 hr and at −5 to 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate (2:9, 100 mL), and dried under reduced pressure at 50° C. to give (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (1R)-1-phenylethylamine salt as a white crystalline powder (55.7 g, yield 69.6%).

1. additionwas added at the same temperature
2. washthe used container was washed with tetrahydrofuran (50.0 mL)
3. customthe mixture was partitioned
4. extractionThe aqueous layer was extracted again with ethyl acetate (125 mL×2)
5. washwashed successively with 20 w/v % aqueous citric acid solution (250 mL) and water (250 mL×2)
6. concentrationThe organic layer was concentrated under reduced pressure
7. additionTo the residue were added ethanol (100 mL) and ethyl acetate (450 mL)
8. temperaturethe mixture was heated to 60-70° C.
9. stirringThe mixture was stirred at 50-60° C. for 1 hr, at 20-30° C. for 1 hr and at −5 to 5° C. for 1 hr
10. filtrationThe precipitated crystals were collected by filtration
11. washwashed with ethanol-ethyl acetate (2:9, 100 mL)
12. customdried under reduced pressure at 50° C.