反应详情

To 100 mg (0.22 mmol) of chloroformate 6-1 in THF was added 130 mg (0.65 mmol) of (+/−)-3-amino-1-N-Boc-piperidine (9-1) and 90 μL (0.65 mmol) of triethylamine. After stirring overnight at room temperature, the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide both diastereomers in pure form. To 35 mg (0.057 mmol) of the first eluting diastereomer in DMF at 0° C. was added 18 μL (0.29 mmol) of MeI and 11 mg (0.29 mmol) of NaH (60% dispersion in oil). After stirring for 3 h at 0° C., the reaction was quenched with saturated NH4Cl, poured into EtOAc, and the layers were separated. The organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was then dissolved in CH2Cl2 and 1 mL of trifluoroacetic acid was added. After stirring for 3 h at room temperature, the solvents were removed, the residue was partitioned between EtOAc and saturated NaHCO3, the organic phase was washed with brine, dried over MgSO4 and concentrated by rotary evaporation. The residue was then purified by silica gel chromatography with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 9-2 as a white solid. Data for 9-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.25 (s, 1H), 4.8 (m, 1H), 4.65 (m, 1H), 4.45 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.1 (m, 2H) 2.9 (s, 3H), 2.6 (m, 2H), 2.1-0.9 (m, 6H) ppm. HRMS (ES) calc'd M+H for C24H27F2N3O2: 428.2144. Found: 428.2132.

1. customthe mixture was partitioned between EtOAc and saturated NaHCO3
2. customthe layers were separated
3. washthe organic phase was washed with water, brine
4. dry with materialdried over MgSO4
5. concentrationconcentrated by rotary evaporation
6. customThe residue was purified by column chromatography on silica gel with EtOAc/hexanes
7. customto provide both diastereomers in pure form
8. stirringAfter stirring for 3 h at 0° C.
9. customthe reaction was quenched with saturated NH4Cl
10. additionpoured into EtOAc
11. customthe layers were separated
12. washThe organic phase was washed with brine
13. dry with materialdried over MgSO4
14. concentrationconcentrated by rotary evaporation
15. dissolutionThe residue was then dissolved in CH2Cl2
16. addition1 mL of trifluoroacetic acid was added
17. stirringAfter stirring for 3 h at room temperature
18. customthe solvents were removed
19. customthe residue was partitioned between EtOAc and saturated NaHCO3
20. washthe organic phase was washed with brine
21. dry with materialdried over MgSO4
22. concentrationconcentrated by rotary evaporation
23. customThe residue was then purified by silica gel chromatography with 20:1:1 EtOH/NH4OH/H2O in EtOAc