2,2-dimethyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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%). 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

反応条件: temp:64.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Two 22 L flasks were each charged with compound 54a (583 g, 2.38 mol), LiOH.H2O (204.5 g, 4.87 mol), THF (5.7 L), and water (4.75 L). The reaction mixtures were heated to 64° C. for 19 h. The mixtures were then cooled to 10° C. with an ice bath. Approximately 1 L of 6N HCl was added to each reaction mixture to bring the pH to 3-3.5. Each mixture was combined with 2.9 L of CH2Cl2, and the aqueous layers were separated. The aqueous layers were extracted with another 1.5 L portion of CH2Cl2. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white solid. The solid was slurried in 5 L of heptane for 1 h, filtered, and vacuum dried to give 830 g (80% yield) of compound 55 as a white solid, mp 114-116° C. Anal. Calcd for C10H19NO4: C, 55.28; H, 8.81; N, 6.45. Found: C, 55.55; H, 8.77; N, 6.56. The reaction mixtures The mixtures were then cooled to 10° C. with an ice bath the aqueous layers were separated The aqueous layers were extracted with another 1.5 L portion of CH2Cl2 The combined organic layers were dried with sodium sulfate concentrated in vacuo to give a white solid filtered vacuum dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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%). 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

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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%). 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

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:64.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Two 22 L flasks were each charged with compound 54a (583 g, 2.38 mol), LiOH.H2O (204.5 g, 4.87 mol), THF (5.7 L), and water (4.75 L). The reaction mixtures were heated to 64° C. for 19 h. The mixtures were then cooled to 10° C. with an ice bath. Approximately 1 L of 6N HCl was added to each reaction mixture to bring the pH to 3-3.5. Each mixture was combined with 2.9 L of CH2Cl2, and the aqueous layers were separated. The aqueous layers were extracted with another 1.5 L portion of CH2Cl2. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white solid. The solid was slurried in 5 L of heptane for 1 h, filtered, and vacuum dried to give 830 g (80% yield) of compound 55 as a white solid, mp 114-116° C. Anal. Calcd for C10H19NO4: C, 55.28; H, 8.81; N, 6.45. Found: C, 55.55; H, 8.77; N, 6.56. The reaction mixtures The mixtures were then cooled to 10° C. with an ice bath the aqueous layers were separated The aqueous layers were extracted with another 1.5 L portion of CH2Cl2 The combined organic layers were dried with sodium sulfate concentrated in vacuo to give a white solid filtered vacuum dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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%). 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