苄基,N-二苄基-L-苯丙氨酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: L-Phenylalanine (50 g), pulverized potassium carbonate (167 34 g), and sodium iodide (22.68 g) were added to N,N-dimethylacetamide (500 ml) while stirring, and water (25 ml) was added thereto. After elevating the temperature to 60° C., benzyl chloride (118.78 g) was dropwise added. After the dropwise addition, the mixture was vigorously stirred at 60°-65° C. for 6 hours. After the reaction, the reaction mixture was cooled to 20°-30° C., and water (750 ml) and ethyl acetate (500 ml) were added thereto for extraction. The ethyl acetate layer was separated, washed with water (500 ml), an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure to give N,N-dibenzyl-L-phenylalanine benzyl ester (136.88 g) as a yellow, oily substance. to 60° C. After the dropwise addition the mixture was vigorously stirred at 60°-65° C. for 6 hours After the reaction the reaction mixture was cooled to 20°-30° C. for extraction The ethyl acetate layer was separated washed with water (500 ml) an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: L-Phenylalanine (50 g), pulverized potassium carbonate (167 34 g), and sodium iodide (22.68 g) were added to N,N-dimethylacetamide (500 ml) while stirring, and water (25 ml) was added thereto. After elevating the temperature to 60° C., benzyl chloride (118.78 g) was dropwise added. After the dropwise addition, the mixture was vigorously stirred at 60°-65° C. for 6 hours. After the reaction, the reaction mixture was cooled to 20°-30° C., and water (750 ml) and ethyl acetate (500 ml) were added thereto for extraction. The ethyl acetate layer was separated, washed with water (500 ml), an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure to give N,N-dibenzyl-L-phenylalanine benzyl ester (136.88 g) as a yellow, oily substance. to 60° C. After the dropwise addition the mixture was vigorously stirred at 60°-65° C. for 6 hours After the reaction the reaction mixture was cooled to 20°-30° C. for extraction The ethyl acetate layer was separated washed with water (500 ml) an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification. The reaction mixture was cooled to 60° C. the lower aqueous layer was removed Heptane (850 L) and water (385 L) were added to the organics, the layers separated The organics were then washed once with a water/methanol mixture (150 L/150 L)

反应条件: temp:74.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74 to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1. cooled to 0° C at 0° C After these were reacted at 0° C. for 30 minutes was thus subjected to phase separation The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate the resulting extract washed with 60 ml of a saturated saline solution This was dried with anhydrous sodium sulfate filtered concentrated the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) crystallized in toluene/hexane

反应条件: temp:74.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74 to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1. cooled to 0° C at 0° C After these were reacted at 0° C. for 30 minutes was thus subjected to phase separation The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate the resulting extract washed with 60 ml of a saturated saline solution This was dried with anhydrous sodium sulfate filtered concentrated the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) crystallized in toluene/hexane

反应条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and then 57.51 g (454.3 mmol) of benzyl chloride was added thereto and stirred under heat at 95° C. for 19 hours. After having been cooled to room temperature, this was subjected to phase separation with 67 ml of n-heptane and 50 ml of water. The organic layer thus separated was washed two times with 50 ml of a solution of methanol/water (=1/2) and then dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 61.64 g (90.5 wt. %, 121.8 mmol) of the above-entitled compound. The yield was 84.7%. After having been cooled to room temperature this was subjected to phase separation with 67 ml of n-heptane and 50 ml of water The organic layer thus separated was washed two times with 50 ml of a solution of methanol/water (=1/2) dried with anhydrous sodium sulfate This was filtered concentrated to obtain 61.64 g (90.5 wt. %, 121.8 mmol) of the above-entitled compound

反应条件: temp:-53.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution (2.0M) (24 ml, 48 mmol) of LDA in heptane, THF and ethyl benzene was dissolved in 64 ml of anhydrous THF, and the mixed solution was cooled to −53° C. in an argon atmosphere. To this solution was added dropwise a solution of 5.8 g (50 mmols) of tert-butyl acetate in 12 ml of THF for approximately 15 minutes, while maintaining the temperature of from −45° C. to −50° C. After the completion of the dropwise addition, the mixture was stirred at −53° C. for 1 hour. Subsequently, a solution of 7.2 g (15 mmols, purity 90%) of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia) in 8 ml of THF was added dropwise thereto for approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C. After the completion of the dropwise addition, the reaction temperature was raised to −5° C. After three hours, a solution of 16.5 g of citric acid in 50 ml of water was added to the reaction solution to stop the reaction. The resulting mixture was extracted twice with ethyl acetate (100 ml and 50 ml), and the organic layer was washed with 20 ml of 10% citric acid, with 10 ml of a saturated aqueous solution of sodium chloride, with 5% sodium hydrogencarbonate aqueous solution (20 ml×4) and with 10 ml of a saturated aqueous solution of sodium chloride in this order. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The concentrate was purified through silica-gel column chromatography (eluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1) to give 6.09 g (13.7 mmol) of the above-mentioned compound (IIa). while maintaining the temperature of from −45° C. to −50° C After the completion of the dropwise addition for approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C After the completion of the dropwise addition the reaction temperature was raised to −5° C After three hours the reaction The resulting mixture was extracted twice with ethyl acetate (100 ml and 50 ml) the organic layer was washed with 20 ml of 10% citric acid, with 10 ml of a saturated aqueous solution of sodium chloride, with 5% sodium hydrogencarbonate aqueous solution (20 ml×4) and with 10 ml of a saturated aqueous solution of sodium chloride in this order The organic layer was dried over anhydrous magnesium sulfate the filtrate was concentrated The concentrate was purified through silica-gel column chromatography ( eluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1)

反应条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Twenty-five grams (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and 57.51 g (454.3 mmol) of benzyl chloride were added thereto. The mixture was heat-stirred at 95° C. for 19 hours. After the reaction mixture was cooled to room temperature, 67 ml of n-heptane and 50 ml of water were added thereto. The organic layer was washed twice with 50 ml of a mixture of methanol and water at a volume ratio of 1:2 and was then dried over anhydrous sodium sulfate. The dried substance was filtered and concentrated to give 61.64 g (90%, 121.8 mmol) of the above-mentioned compound (Ia) in a yield of 84.7%. After the reaction mixture was cooled to room temperature The organic layer was washed twice with 50 ml of a mixture of methanol and water at a volume ratio of 1:2 was then dried over anhydrous sodium sulfate The dried substance was filtered concentrated

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification. The reaction mixture was cooled to 60° C. the lower aqueous layer was removed Heptane (850 L) and water (385 L) were added to the organics, the layers separated The organics were then washed once with a water/methanol mixture (150 L/150 L)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification. The reaction mixture was cooled to 60° C. the lower aqueous layer was removed Heptane (850 L) and water (385 L) were added to the organics, the layers separated The organics were then washed once with a water/methanol mixture (150 L/150 L)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: L-Phenylalanine (50 g), pulverized potassium carbonate (167 34 g), and sodium iodide (22.68 g) were added to N,N-dimethylacetamide (500 ml) while stirring, and water (25 ml) was added thereto. After elevating the temperature to 60° C., benzyl chloride (118.78 g) was dropwise added. After the dropwise addition, the mixture was vigorously stirred at 60°-65° C. for 6 hours. After the reaction, the reaction mixture was cooled to 20°-30° C., and water (750 ml) and ethyl acetate (500 ml) were added thereto for extraction. The ethyl acetate layer was separated, washed with water (500 ml), an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure to give N,N-dibenzyl-L-phenylalanine benzyl ester (136.88 g) as a yellow, oily substance. to 60° C. After the dropwise addition the mixture was vigorously stirred at 60°-65° C. for 6 hours After the reaction the reaction mixture was cooled to 20°-30° C. for extraction The ethyl acetate layer was separated washed with water (500 ml) an aqueous solution of 10% sodium hydrogensulfite (500 ml×2), and water (500 ml), and concentrated to dryness under reduced pressure

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (365 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification. The reaction mixture was cooled to 60° C. the lower aqueous layer was removed Heptane (850 L) and water (365 L) were added to the organics, the layers separated The organics were then washed once with a water/methanol mixture (150 L/150 L)