N-[(4-methoxyphenyl)methyl]hydroxylamine

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves on stirring The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

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

実験手順: 1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C). the mixture was then concentrated under a reduced pressure 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue the aqueous layer was separated concentrated under a reduced pressure to a small volume The crystals precipitated were collected by filtration

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves on stirring The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves on stirring The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

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

実験手順: 1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C). the mixture was then concentrated under a reduced pressure 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue the aqueous layer was separated concentrated under a reduced pressure to a small volume The crystals precipitated were collected by filtration

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

実験手順: 1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C). the mixture was then concentrated under a reduced pressure 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue the aqueous layer was separated concentrated under a reduced pressure to a small volume The crystals precipitated were collected by filtration

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stiffing for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves on stirring The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stirring for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield). The reaction is cooled to room temperature A solid precipitates which then re-dissolves on stirring The biphasic mixture is separated the aqueous layer is extracted with ethyl acetate (2×1 L) The combined organic layers are washed with water (2×2 L), brine dried over Na2SO4 filtered concentrated to dryness The residue is dissolved in ethyl acetate (3 L) concentrated under reduced pressure again The crude product is triturated in ethyl acetate (1.2 L) isohexane (4.8 L) for 40 minutes The suspension is filtered washed with hexane (4 L) The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

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

実験手順: 1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C). the mixture was then concentrated under a reduced pressure 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue the aqueous layer was separated concentrated under a reduced pressure to a small volume The crystals precipitated were collected by filtration