反应详情

To tert-butyl[1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate (28.9 g, 101 mmol) were added methyl 1-aminocyclopentanecarboxylate (43.4 g, 303 mmol) followed by titanium(IV) isopropoxide (44.5 mL, 152 mmol) and the reaction mixture was stirred at ambient temperature for 90 min, diluted with MeOH (130 mL), and cooled in an ice-water bath. To this stirred mixture were added AcOH (29 mL, 507 mmol) followed by NaCNBH3 (7.64 g, 122 mmol), portionwise, over 5 min. Stirring was continued for 5 min, then the ice-water bath was removed, and stirring was continued for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 L) and extracted with EtOAc (3×1.5 L). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 50:50, to give a mixture of the title compound and the corresponding isopropyl ester. MS: m/z=413 (M+1).

1. temperaturecooled in an ice-water bath
2. waitportionwise, over 5 min
3. stirringStirring
4. waitwas continued for 5 min
5. customthe ice-water bath was removed
6. stirringstirring
7. waitwas continued for 30 min
8. customThe reaction mixture was quenched with saturated aqueous NaHCO3 (1 L)
9. extractionextracted with EtOAc (3×1.5 L)
10. washThe combined organic extracts were washed with brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe crude product was purified by silica gel chromatography
15. washeluting with hexane
16. customEtOAc—100:0 to 50:50, to give