反应详情

Following a procedure similar to that disclosed in U.S. Pat. No. 3,962,449, a three-necked, 50-mL, round-bottomed flask was fitted with a dropping funnel (60 mL), a condenser with an N2 inlet, a heating mantle, and a magnetic stirrer. This flask was charged with a solution of benzylamine (2.68 g, 25.0 mmol) and glacial acetic acid (1.54 g, 25.8 mmol) in methanol (25 mL). To this solution was added paraformaldehyde (1.58 g, 52.5 mmol); then the apparatus was flushed with N2 and the mixture was brought to reflux with stirring. After 15 min, a solution of 1-benzyl-4-piperidone (4.73 g, 25.0 mmol) and glacial acetic acid (1.50 g, 25.0 mmol) in methanol (18 mL) was added over 0.5 hours. The resulting orange solution was then boiled at reflux for an additional 9.5 hours. The mixture was then cooled to room temperature and the solvent was evaporated (aspirator) to give an orange oil. Water (50 mL) and KOH pellets (85%, 3.30 g, 50.0 mmol) was added, and the resulting oily, orange suspension was extracted (CH2Cl2, 3×50 mL). The organic extracts were combined and dried (MgSO4, overnight). Filtration of the mixture followed by evaporation (aspirator) afforded an orange oil which was vacuum distilled (8×10-7 mm Hg, diffusion pump). At 106°-108° C. there was collected a colorless oil (0.36 g), the 13C NMR of which was identical to 1-benzyl-4-piperidone. A second fraction (bp 180°-205° C.) was collected as a yellow oil but with substantial decomposition of the residue. This second fraction was redistilled (180°-185° C., 1.0×10-6 mm Hg) to yield again a yellow oil. This oil was dissolved in hot Skelly B (80 mL) and, upon cooling to -10° C., pure N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (2.53 g, 31.6%) was precipitated as a white solid: mp 61°-63° C. (literature 70°-71° C.). The compound was used in the next step without further purification. The spectroscopic data for this compound were: IR (KBr) cm-1 2963, 2822, 1738, 1721, 748, 703 1H NMR (DCCl3) δ2.52 [br s, 2H, H(1,5)], 2.77, 278 [two d, J=10.7 Hz, 4H, H(2,4,6,8)ax], 3.00 [br d, J=10.5 Hz, 4H, H(2,4,6,8)eq], 3.53 [s, 4H, ArCH2 ], 7.23-7.30 [m, 10H, ArH]; 13C NMR (DCCl3) ppm 46.7 [d, C(1,5)], 58.01 [t, C(2,4,6,8)], 61.1 [t, ArCH2 ], 126.90 [d, p-ArC], 128.02 [d, o- or m-ArC], 128.53 [d, m- or o-ArC] 138.02 [s, i-ArC], 214.0 [s, C(9)]; 15N NMR (DCCl3) ppm 39.25 [N(3,7)].

1. custom3,962,449, a three-necked, 50-mL, round-bottomed flask was fitted with a dropping funnel (60 mL), a condenser with an N2 inlet
2. customthen the apparatus was flushed with N2
3. temperatureto reflux
4. temperatureat reflux for an additional 9.5 hours
5. customthe solvent was evaporated (aspirator)
6. customto give an orange oil
7. extractionthe resulting oily, orange suspension was extracted (CH2Cl2, 3×50 mL)
8. dry with materialdried (MgSO4, overnight)
9. filtrationFiltration of the mixture
10. customfollowed by evaporation (aspirator)
11. customafforded an orange oil which
12. distillationdistilled (8×10-7 mm Hg, diffusion pump)
13. customAt 106°-108° C. there was collected a colorless oil (0.36 g)
14. customA second fraction (bp 180°-205° C.) was collected as a yellow oil but with substantial decomposition of the residue
15. distillationThis second fraction was redistilled (180°-185° C., 1.0×10-6 mm Hg)
16. customto yield again a yellow oil
17. dissolutionThis oil was dissolved in hot Skelly B (80 mL)
18. temperatureupon cooling to -10° C.
19. custompure N,N'-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (2.53 g, 31.6%) was precipitated as a white solid
20. custommp 61°-63° C. (literature 70°-71° C.)
21. customThe compound was used in the next step without further purification