4-[(1R)-1-aminoethyl]phenol

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

実験手順: Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH2Cl2 (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by TLC, the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL), dried over Na2SO4, filtered and concentrated to yield 30.1 g (61.9 mmol; 93%) of the sub-title compound. the solution was concentrated under vacuum to give the crude product washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL) dried over Na2SO4 filtered concentrated

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

実験手順: Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH2Cl2 (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by TLC, the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL), dried over Na2SO4, filtered and concentrated to yield 30.1 g (61.9 mmol; 93%) of the sub-title compound. the solution was concentrated under vacuum to give the crude product washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL) dried over Na2SO4 filtered concentrated

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (R)-1-(4-tert-Butoxyphenyl)ethylamine (89.4 g, 0.463 mol) was dissolved in 10% hydrochloric acid (200 ml) and heated to 85° C. At approx. 80° C., vigorous gas evolution set in. The mixture was stirred at 85° C. for another three hours, after which the gas evolution had stopped. The pale yellow mixture was allowed to cool to room temperature and then 20% NaOH was added dropwise up to a pH of 10.2. The deprotected phenol precipitated out overnight in the form of a pale yellow powder. It was filtered off with suction and dried in a drying cabinet overnight. For purification, the crude product was digested with tert-butyl methyl ether (200 ml). The suspension was filtered and the filter residue was dried again under reduced pressure. 51.3 g (63%) of (R)-4-(1-aminoethyl)phenol were obtained in the form of a pale yellow powder. At approx. 80° C. to cool to room temperature The deprotected phenol precipitated out overnight in the form of a pale yellow powder It was filtered off with suction dried in a drying cabinet overnight For purification The suspension was filtered the filter residue was dried again under reduced pressure

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.00 g (7.29 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 1.12 g (7.29 mmole) of N-hydroxybenzotriazole monohydrate and 1.51 g (7.29 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 1.96 g (7.29 mmole) of (4R)-3-benzoyl-1,1-dioxothiazolidine-4-carboxylic acid (prepared as described in Preparation 12) in 100 ml of dimethylformamide cooled at 5° C., and then the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 23 hours. The reaction mixture was filtered, the insolubles were washed with 20 ml of ethyl acetate, and the filtrate and the washings were combined. 50 ml of ethyl acetate were added to the combined mixture, which was washed twice, each time with 50 ml of a 4% w/v aqueous solution of sodium bicarbonate, and the organic phase was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by Lobar column chromatography through silica gel (Merck, Art-10402), eluted with a 2:1 by volume mixture of ethyl acetate and cyclohexane. The eluate was concentrated by evaporation under reduced pressure and the residue was lyophilized with a mixture of acetone and benzene to give 2.04 g (72.0%) of the title compound in the form of a colorless powder. at room temperature for a further 23 hours The reaction mixture was filtered the insolubles were washed with 20 ml of ethyl acetate 50 ml of ethyl acetate were added to the combined mixture, which was washed twice each time with 50 ml of a 4% w/v aqueous solution of sodium bicarbonate, and the organic phase was separated dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the residue was purified by Lobar column chromatography through silica gel (Merck, Art-10402) eluted with a 2:1 by volume mixture of ethyl acetate and cyclohexane The eluate was concentrated by evaporation under reduced pressure the residue was lyophilized with a mixture of acetone and benzene

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.47 g (69.11 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 10.58 g (69.11 mmole) of N-hydroxybenzotriazole monohydrate and 14.26 g (69.11 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 17.50 g (69.11 mmole) of (1R,4R)-3-benzoyl-1-oxo-thiazolidine-4-carboxylic acid (prepared as described in Preparation 10) in 100 ml of dimethylformamide cooled at 5° C., and the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 4 hours. At the end of this time, the reaction mixture was filtered and the insolubles were washed with 100 ml of hot dimethylformamide. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure to leave crystals. These crystals were recrystallized from methanol to give 19.21 g (74.6%) of the title compound in the form of colorless needles melting at 233°-234° C. at room temperature for a further 4 hours At the end of this time, the reaction mixture was filtered the insolubles were washed with 100 ml of hot dimethylformamide concentrated by evaporation under reduced pressure to leave crystals These crystals were recrystallized from methanol

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

実験手順: 277 ml of a cooled 20% w/v aqueous solution of sodium hydroxide were added dropwise to 75.2 g (0.277 mole) of (R)-α-methyl-p-hydroxybenzylamine L-malate [obtained as described in step (c) above], and then the mixture was stirred at a temperature between 2° and 5° C. for 15 hours. At the end of this time, 60 g of sodium chloride were added, and the whole mixture was stirred at a temperature between 2° and 5° C. for a further 15 minutes. The crystals which precipitated were collected by filtration, and washed in turn with 100 ml of cold water and 100 ml of acetone to give 32.3 g (85.2%) of the title compound in the form of a colorless powder melting at 124°-125° C. the whole mixture was stirred at a temperature between 2° and 5° C. for a further 15 minutes The crystals which precipitated were collected by filtration washed in turn with 100 ml of cold water and 100 ml of acetone

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

実験手順: Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH2Cl2 (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by TLC, the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL), dried over Na2SO4, filtered and concentrated to yield 30.1 g (61.9 mmol; 93%) of the sub-title compound. the solution was concentrated under vacuum to give the crude product washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL) dried over Na2SO4 filtered concentrated