反应详情

A mixture of 3-benzyl-3-aza-bicyclo[3.2.1]octan-8-one (0.560 g, 2.60 mmol) (Lowe, J. A. et al. J. Med. Chem. 1994, 37, 2831-2840), NH4OAc (2.3 g, 30 mmol) and NaBH3CN (0.245 g, 3.90 mmol) in MeOH (15 mL) was stirred and heated at reflux for 72 h. The mixture was cooled to room temperature, and the solvent was removed. Aqueous NaOH (1 N, 10 mL) was added, and the aqueous suspension was extracted with CH2Cl2 (3×30 mL). The combined extract was washed with water (30 mL) and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was dissolved in dry CH2Cl2 (30 mL). Et3N (3 mL) and Boc2O (0.872 g, 4.00 mmol) were added, and the mixture was stirred for 16 h. Water (30 mL) was then added, and the mixture was extracted with CH2Cl2 (4×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (1:1 CH2Cl2/hexanes), affording an impure solid mainly containing (3-benzyl-3-aza-bicyclo[3.2.1]oct-8-yl)-carbamic acid tert-butyl ester. A mixture of the solid and Pd/C (10% in wt, 0.20 g, 0.188 mmol) in MeOH/EtOAc (40 mL, 3:1) was stirred under H2 atmosphere (1 atm) overnight. CH2Cl2 (20 mL) was then added, and the mixture was filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:1 CH2Cl2/MeOH/NH4OH), affording (3-aza-bicyclo[3.2.1]oct-8-yl)-carbamic acid tert-butyl ester as a white solid (0.277 g, 50%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.62-1.68 (m, 2H), 1.81-1.85 (m, 2H), 2.02 (s, br. 2H), 2.49-2.55 (m, 2H), 2.96-3.01 (m, 2H), 3.67-3.80 (m, 1H), 5.04 (s, br. 1H).

1. temperatureheated
2. temperatureat reflux for 72 h
3. customthe solvent was removed
4. additionAqueous NaOH (1 N, 10 mL) was added
5. extractionthe aqueous suspension was extracted with CH2Cl2 (3×30 mL)
6. extractionThe combined extract
7. washwas washed with water (30 mL)
8. dry with materialdried over anhydrous Na2SO4
9. filtrationAfter filtration the solvent
10. customwas removed by evaporation under vacuum
11. dissolutionthe residue was dissolved in dry CH2Cl2 (30 mL)
12. extractionthe mixture was extracted with CH2Cl2 (4×30 mL)
13. dry with materialdried over anhydrous Na2SO4
14. filtrationAfter filtration the solvent
15. customwas removed by evaporation under vacuum
16. customthe residue was purified by flash chromatography on a silica gel column (1:1 CH2Cl2/hexanes)