反应详情

Methyl 2,2-dimethyl-cyanoacetate (2.0 g) was stirred under a hydrogen atmosphere in a 1N ammonium-containing methanol/ethanol (1:1) mixed solution under the presence of rhodium-alumina catalyst at a room temperature for 6 hours. The catalyst was removed from the reaction solution by filtration and the solvents were distilled off. To the residue were added 4N caustic soda (3 ml) and dioxane (3 ml) and the mixture was stirred at a room temperature for 6 hours. To the resulting mixture were added a 2N aqueous solution of sodium carbonate (25 ml) and di-t-butyl carbonate (2.9 g) dissolved in dioxane (20 ml) and the mixture was stirred for 12 hours. After the solvents were distilled off from the reaction solution, the residue was dissolved in water, washed with ether and adjusted to pH 3 with citric acid under cooling with ice, followed by extraction three times with ethyl acetate. The organic layer was washed with saturated NaCl three times and dried over sodium sulfate. The solvents were distilled off to yield N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (2.5 g). The obtained N-t-butoxycarbonyl-α,α-dimethyl-β-alanine (1.1 g), 4-piperidineacetic acid benzyl ester tosylate (1.52 g), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop, 2.20 g) and triethylamine (1.7 ml) were dissolved in methylene chloride (15 ml) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was applied to a silica gel column (φ 2.5×40 cm, Si-60, eluent: 30% ethyl acetate/hexane) for purification to yield N-(N-t-butoxycarbonyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (1.55 g, 96.0%).

1. distillationAfter the solvent was distilled off
2. customthe residue was applied to a silica gel column (φ 2.5×40 cm, Si-60, eluent: 30% ethyl acetate/hexane) for purification