反应详情

Under a stream of nitrogen N,N′-carbonyldiimidazole (3.62 g, 22.3 mmol) followed by piperidine (3.74 g, 43.9 mmol) is added to a solution of 1-(tert-butoxycarbonyl)-4-phenyl-4-piperidinecarboxylic acid (3.40 g, 11.1 mmol) in dry THF (50 mL). The mixture is heated to reflux 18 h, then cooled to ambient temperature and concentrated by means of evaporation. The remanence is redissolved in ethyl acetate (150 mL) and successively washed with NaHCO3 (50 mL, aq, sat.), dilute HCl (50 mL) at pH 3, brine (50 mL), then dried (MgSO4) and evaporated to dryness. This intermediate is purified by silica gel chromatography eluting with ethyl acetate-heptane-triethylamine (40:50:10) to furnish 1.01 g (24%) of 4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester as a white crystalline solid. This is dissolved in a mixture of MeOH (10 mL) and THF (10 mL), then 2M HCl in MeOH (5 mL) is added and the mixture is stirred at ambient temperature for 2 h. Water (20 mL) is added and pH is adjusted to pH 12 by addition of 2M NaOH. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (30 mL). Combined organic fractions are dried (MgSO4) and concentrated in vacuo to furnish 0.47 g (63%) of (4-Phenyl-piperidine-4-yl)-piperidin-1-yl-methanone. LC/MS (m/z) 273.1 (M+H+); tR=1.65 mm.

1. temperatureThe mixture is heated
2. temperatureto reflux 18 h
3. concentrationconcentrated by means of evaporation
4. dissolutionThe remanence is redissolved in ethyl acetate (150 mL)
5. washsuccessively washed with NaHCO3 (50 mL, aq, sat.), dilute HCl (50 mL) at pH 3, brine (50 mL)
6. dry with materialdried (MgSO4)
7. customevaporated to dryness
8. customThis intermediate is purified by silica gel chromatography
9. washeluting with ethyl acetate-heptane-triethylamine (40:50:10)