2-(Hydroxymethyl)hexanoic acid

反応条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet, and heating mantle is charged with (R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) and ethyl acetate (1.63 L). The solution is stirred and heated to an internal temperature at 60-65° C., and a solution of (±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L) is added over a period of 15 min while maintaining the internal temperature at 60-70° C. The addition funnel is washed with ethyl acetate (0.2 L) and added to the mixture. The solution is cooled to 20-25° C. over a period of 2 hours and the resulting suspension is stirred at the same temperature for an additional 5 hours. The solids are collected by filtration, washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each, and dried at 50-53° C. (13-49 mbar) to afford crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 246.3 g; 41.7%); (R):(S)=94.1:5.9. A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet heating mantle while maintaining the internal temperature at 60-70° C The addition funnel is washed with ethyl acetate (0.2 L) added to the mixture The solution is cooled to 20-25° C. over a period of 2 hours the resulting suspension is stirred at the same temperature for an additional 5 hours The solids are collected by filtration washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each dried at 50-53° C. (13-49 mbar)

反応条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet, and heating mantle is charged with (R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) and ethyl acetate (1.63 L). The solution is stirred and heated to an internal temperature at 60-65° C., and a solution of (±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L) is added over a period of 15 min while maintaining the internal temperature at 60-70° C. The addition funnel is washed with ethyl acetate (0.2 L) and added to the mixture. The solution is cooled to 20-25° C. over a period of 2 hours and the resulting suspension is stirred at the same temperature for an additional 5 hours. The solids are collected by filtration, washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each, and dried at 50-53° C. (13-49 mbar) to afford crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 246.3 g; 41.7%); (R):(S)=94.1:5.9. A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet heating mantle while maintaining the internal temperature at 60-70° C The addition funnel is washed with ethyl acetate (0.2 L) added to the mixture The solution is cooled to 20-25° C. over a period of 2 hours the resulting suspension is stirred at the same temperature for an additional 5 hours The solids are collected by filtration washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each dried at 50-53° C. (13-49 mbar)

反応条件: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step. A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer while maintaining the internal temperature at 15-25° C The reaction mixture is cooled to an internal temperature at 10-13° C. quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent

反応条件: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step. A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer while maintaining the internal temperature at 15-25° C The reaction mixture is cooled to an internal temperature at 10-13° C. quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent

反応条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet, and heating mantle is charged with (R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) and ethyl acetate (1.63 L). The solution is stirred and heated to an internal temperature at 60-65° C., and a solution of (±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L) is added over a period of 15 min while maintaining the internal temperature at 60-70° C. The addition funnel is washed with ethyl acetate (0.2 L) and added to the mixture. The solution is cooled to 20-25° C. over a period of 2 hours and the resulting suspension is stirred at the same temperature for an additional 5 hours. The solids are collected by filtration, washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each, and dried at 50-53° C. (13-49 mbar) to afford crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 246.3 g; 41.7%); (R):(S)=94.1:5.9. A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet heating mantle while maintaining the internal temperature at 60-70° C The addition funnel is washed with ethyl acetate (0.2 L) added to the mixture The solution is cooled to 20-25° C. over a period of 2 hours the resulting suspension is stirred at the same temperature for an additional 5 hours The solids are collected by filtration washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each dried at 50-53° C. (13-49 mbar)

反応条件: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step. A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer while maintaining the internal temperature at 15-25° C The reaction mixture is cooled to an internal temperature at 10-13° C. quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent

反応条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet, and heating mantle is charged with (R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) and ethyl acetate (1.63 L). The solution is stirred and heated to an internal temperature at 60-65° C., and a solution of (±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L) is added over a period of 15 min while maintaining the internal temperature at 60-70° C. The addition funnel is washed with ethyl acetate (0.2 L) and added to the mixture. The solution is cooled to 20-25° C. over a period of 2 hours and the resulting suspension is stirred at the same temperature for an additional 5 hours. The solids are collected by filtration, washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each, and dried at 50-53° C. (13-49 mbar) to afford crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 246.3 g; 41.7%); (R):(S)=94.1:5.9. A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet heating mantle while maintaining the internal temperature at 60-70° C The addition funnel is washed with ethyl acetate (0.2 L) added to the mixture The solution is cooled to 20-25° C. over a period of 2 hours the resulting suspension is stirred at the same temperature for an additional 5 hours The solids are collected by filtration washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each dried at 50-53° C. (13-49 mbar)

反応条件: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, and nitrogen inlet-outlet is charged with 2-butyl-propanedioic acid monoethyl ester (3, 450.0 g, 2.39 mol) and isopropanol (4.5 L). The solution is cooled to an internal temperature at 15-18° C. and a 2 M solution of lithium borohydride (2.4 L, 4.8 mol) in tetrahydrofuran is added over a period of 1.5 hours while maintaining the internal temperature at 15-25° C. The stirring is continued for an additional 3 h. The reaction mixture is cooled to an internal temperature at 10-13° C. and quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C. The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent to obtain a suspension (˜1.9 kg). This suspension is diluted with water (2.0 L) and ethyl acetate (2.5 L) and the biphasic mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2.0 L). The combined organic layers are washed with 20% aqueous solution of sodium chloride (1.0 L) and concentrated under vacuum (20 mbar) until no further solvent distills to afford crude (±)-2-butyl-3-hydroxypropionic acid (4, 349.4 g, 100%) as a colorless liquid, which is used as such in the next step. A 12 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer while maintaining the internal temperature at 15-25° C The reaction mixture is cooled to an internal temperature at 10-13° C. quenched by the addition of 2 N HCl (2.4 L) over a period of 1 hour while maintaining the internal temperature at 10-25° C The reaction mixture is concentrated at 35-40° C. (20 mbar) to collect ˜7.5 L of the solvent