N-[(1S)-1-[(1S)-2-(环丙基氨基)-1-羟基-2-氧代乙基]丁基]氨基甲酸叔丁酯

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (46.1 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (34.82 g). Hexane (20 g) was added to the solution and the mixture was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (9.1 g) was dropwise added, taking 1 hour. Then, after stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 4 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (15 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (3.48 g, yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee). the reaction solution was cooled down to 0° C. at a constant rate taking about 6 hours The precipitated crystals were collected by filtration under reduced pressure (diameter 4 cm, filter pore size 4 μm) the time taken for separation of the crystals from the mother liquid was about 30 seconds The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (15 mL) Next, the washed wet crystals were dried in vacuum at 60° C.

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (92.2 g, 10.8 wt. %) obtained in the above Example 2 was used. The solvent was changed from ethyl acetate to isopropyl alcohol, thereby to prepare an isopropyl alcohol solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (69.63 g). The solution was heated up to 60° C., and 10.5 wt % hydrogen chloride/isopropyl alcohol solution (18.2 g) was dropwise added, taking 1 hour. After stirred for 8 hours, the reaction solution was cooled down to 0° C. at a constant rate, taking about 6 hours. The slurry had no solid aggregation therein, and had good flowability. The precipitated crystals were collected by filtration under reduced pressure, using a kiriyama funnel (diameter 6 cm, filter pore size 4 μm). At the time, the filterability was good, and the time taken for separation of the crystals from the mother liquid was about 30 seconds. The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (30 mL). Next, the washed wet crystals were dried in vacuum at 60° C., to obtain (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (7.06 g, isolation yield: 90 mol %, chemical purity: 100.0 area %, optical purity: 100% ee). the reaction solution was cooled down to 0° C. at a constant rate taking about 6 hours The precipitated crystals were collected by filtration under reduced pressure (diameter 6 cm, filter pore size 4 μm) the time taken for separation of the crystals from the mother liquid was about 30 seconds The obtained wet crystals were washed with hexane/isopropyl alcohol=1/1 solution (30 mL) Next, the washed wet crystals were dried in vacuum at 60° C.

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Isopropanol (250 mL) was added to (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (26.5 g, 92.54 mmol), and the mixture was heated up to about 60° C. To the solution, 35% hydrochloric acid aqueous solution (14.5 g, 138.8 mmol) was dropwise added, and the mixture was stirred for 24 hours. After the disappearance of the starting material, the reaction liquid for the remove of Boc function group was cooled from 60° C. to 2° C. at a constant cooling rate, taking about 6 hours. As a result, no solid aggregated and the flowability thereof was good. The precipitated crystals were collected by filtration under reduced pressure, using a Kiriyama funnel (diameter 6 cm, filter pore size 4 μm). At the time, the filterability was good and the time for the separation of the crystals from the mother liquid was about 60 seconds. By the isolation and drying in vacuum, (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (16.53 g) was obtained as white crystals (yield: 80 mol %, isopropanol content: no isopropanol detected, chemical purity: 100.0 area %, optical purity: 100% ee). After the disappearance of the starting material, the reaction liquid for the remove of Boc function group was cooled from 60° C. to 2° C. at a constant cooling rate taking about 6 hours The precipitated crystals were collected by filtration under reduced pressure a Kiriyama funnel (diameter 6 cm, filter pore size 4 μm) the time for the separation of the crystals from the mother liquid was about 60 seconds By the isolation and drying in vacuum

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Cyclopropylamine (2.77 g, 48.53 mmol) was dropwise added to an ethyl acetate (108 g) solution of (2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid (10.0 g, 40.44 mmol). The mixture was cooled by ice. A mixed solution of HOBt monohydrate (1.86 g, 12.13 mmol)/THF (9.3 g)/water (1.9 g)=1/5/1 and a mixed solution of EDC hydrochloride (8.53 g, 44.48 mmol)/water (8.5 g)=1/1 were dropwise added in that order, and the mixture was stirred for 14 hours with cooling by ice. Next, 5% NaHCO3 aqueous solution (50 g) was added, and the mixture was heated up to 40° C. Then, the aqueous layer was removed. The organic layer was washed once with 5% NaHCO3 aqueous solution (50 g) at 40° C., and finally washed with water (50 g), to obtain a solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (reaction yield: 97 mol %, extraction yield: 98 mol %, chemical purity: 96.0 area %). The mixture was cooled by ice with cooling by ice Then, the aqueous layer was removed The organic layer was washed once with 5% NaHCO3 aqueous solution (50 g) at 40° C. finally washed with water (50 g)

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Cyclopropylamine (1.99 g, 34.94 mmol) was dropwise added to a mixed solution of (2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid (7.2 g, 29.12 mmol), ethyl acetate (144 g) and water (7.2 g). The mixture was cooled by ice. HOBt monohydrate (4.68 g, 30.58 mmol) and EDC hydrochloride (6.14 g, 32.03 mmol) were added thereto, and the mixture was stirred with cooling by ice for 22 hours. Next, 5% NaHCO3 aqueous solution (72 g) was added thereto, and the mixture was heated up to 40° C. Then, the aqueous layer was removed. The organic layer was washed twice with 5% NaHCO3 aqueous solution (72 g) at 40° C., and finally the organic layer was washed with water (72 g), to obtain an ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (yield: 90 mol %, chemical purity: 96.1 area %, optical purity: 99.3% ee). The obtained organic layer (140.2 g) was concentrated under reduced pressure to be 62.5 g, using a rotary evaporator. The obtained slurry was heated up to 60° C. so as to dissolve the contents, and then cooled to 51° C. Seed crystals of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (2 mg) were added to the solution. As a result, crystals were gradually precipitated. The mixture was aged at the same temperature for 1 hour, and then was cooled to 2° C., taking about 5 hours. The precipitated crystals were separated and dried to obtain (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (6.45 g, isolation yield: 78 mol %, chemical purity: 100.0 area %, optical purity: 100% ee). The mixture was cooled by ice with cooling by ice for 22 hours Then, the aqueous layer was removed The organic layer was washed twice with 5% NaHCO3 aqueous solution (72 g) at 40° C. finally the organic layer was washed with water (72 g)

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

实验步骤: To a 4 M 1,4-dioxane solution (60 mL) of hydrogen chloride, (2S,3S)—N-cyclopropyl-3-(t-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (4.5 g) was added. A solid of the product aggregated to form a lump after about 5 minutes, and the flowability of the reaction liquid worsened. After the disappearance of the starting material, the solvent was evaporated away with an evaporator to obtain a concentrated product of (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (chemical purity: 89.8 area %). to form a lump after about 5 minutes the flowability of the reaction liquid After the disappearance of the starting material, the solvent was evaporated away with an evaporator

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

实验步骤: Cyclopropylamine (55 mg, 0.97 mmol) was dropwise added to an ethyl acetate (5 mL) solution of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxyhexanoic acid (200 mg, 0.81 mmol), and the mixture was cooled by ice. HOBt monohydrate (130 mg, 0.85 mmol) and EDC hydrochloride (171 mg, 0.89 mmol) were added thereto, and the mixture was stirred with cooling by ice. As a result, the solid in the mixture aggregated to form a hard lump after about 5 minutes, and the mixture became impossible to be stirred. the mixture was cooled by ice with cooling by ice to form a hard lump after about 5 minutes to be stirred