(2R)-2-(hydroxymethyl)hexanoic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0 mL) is added to the mixture. After mixing for 5 min, the organic layer is separated and the aqueous layer is extracted with isopropyl acetate (3×50.0 mL). The combined organic layers are washed with water (20.0 mL) and concentrated under vacuum (20 mbar) until no further solvent distills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%); oil; [α]D+6.5 (c=1.0, CH3OH), (R):(S)=99.3:0.7. After mixing for 5 min the organic layer is separated the aqueous layer is extracted with isopropyl acetate (3×50.0 mL) The combined organic layers are washed with water (20.0 mL) concentrated under vacuum (20 mbar) until no further solvent distills

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0 mL) is added to the mixture. After mixing for 5 min, the organic layer is separated and the aqueous layer is extracted with isopropyl acetate (3×50.0 mL). The combined organic layers are washed with water (20.0 mL) and concentrated under vacuum (20 mbar) until no further solvent distills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%); oil; [α]D+6.5 (c=1.0, CH3OH), (R):(S)=99.3:0.7. After mixing for 5 min the organic layer is separated the aqueous layer is extracted with isopropyl acetate (3×50.0 mL) The combined organic layers are washed with water (20.0 mL) concentrated under vacuum (20 mbar) until no further solvent distills

Conditions: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]D25=+0.556 (c, 1.0, MeOH). A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer to give a cloudy solution while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.) Wash the funnel once with 50 mL of water Stir the thick suspension at 20° C.±3° C. for 2 hours Filter the solids through a polypropylene filter cloth a Büchner funnel then wash the flask filter cake once with 0.5 L of water Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours

Conditions: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]D25=+0.556 (c, 1.0, MeOH). A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer to give a cloudy solution while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.) Wash the funnel once with 50 mL of water Stir the thick suspension at 20° C.±3° C. for 2 hours Filter the solids through a polypropylene filter cloth a Büchner funnel then wash the flask filter cake once with 0.5 L of water Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0 mL) is added to the mixture. After mixing for 5 min, the organic layer is separated and the aqueous layer is extracted with isopropyl acetate (3×50.0 mL). The combined organic layers are washed with water (20.0 mL) and concentrated under vacuum (20 mbar) until no further solvent distills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%); oil; [α]D+6.5 (c=1.0, CH3OH), (R):(S)=99.3:0.7. After mixing for 5 min the organic layer is separated the aqueous layer is extracted with isopropyl acetate (3×50.0 mL) The combined organic layers are washed with water (20.0 mL) concentrated under vacuum (20 mbar) until no further solvent distills

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3000 mL roundbottom flask was added (2R)-2-(hydroxymethyl)hexanoic acid (5) (77 g, 0.527 mol) in THF/water (4:1, 1800 mL), followed by benzylhydroxylamine hydrochloride (100 g, 0.632 mol). The mixture was cooled to 0° C. and was adjusted with 1 N HCl to pH ˜4.5. EDCI (202 g, 1.05 mol) was added in one portion. The mixture was stirred at 0° C. for 2 h, while the pH of the mixture was maintained at ˜4.5 by addition of 1 N HCl. THF was then removed under vacuum, and the white solid was collected by filtration to afford the titled compound as a crude mixture (100 g). Further purification by flash column eluting with ethyl acetate/petroleum ether (1:10) provided the pure product (52 g, 39%). LCMS: (M+H)+: 252.2. THF was then removed under vacuum the white solid was collected by filtration

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 2000 mL roundbottom flask was added (4S)-3-[(2R)-2-(hydroxymethyl)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (4) (82 g, 0.268 mol) in THF/water (4:1, 750 mL). The solution was cooled to 0° C. and H2O2 (130 mL, 1.07 mol) was added dropwise, followed by lithium hydroxide monohydrate (22.58 g, 0.537 mol) in water (130 mL). The reaction mixture was warmed up to rt and stirred overnight. THF was removed under vacuum, and the aqueous solution was washed with ethyl acetate. The aqueous solution was then acidified to pH ˜3.0 and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated to provide the title compound (42 g, 107%). LCMS: (2M+H)+: 313.2. The reaction mixture was warmed up to rt THF was removed under vacuum the aqueous solution was washed with ethyl acetate extracted with ethyl acetate The extracts were dried (Na2SO4) filtered concentrated

Conditions: temp:16.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]D25=+0.556 (c, 1.0, MeOH). A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer to give a cloudy solution while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.) Wash the funnel once with 50 mL of water Stir the thick suspension at 20° C.±3° C. for 2 hours Filter the solids through a polypropylene filter cloth a Büchner funnel then wash the flask filter cake once with 0.5 L of water Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0 mL) is added to the mixture. After mixing for 5 min, the organic layer is separated and the aqueous layer is extracted with isopropyl acetate (3×50.0 mL). The combined organic layers are washed with water (20.0 mL) and concentrated under vacuum (20 mbar) until no further solvent distills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%); oil; [α]D+6.5 (c=1.0, CH3OH), (R):(S)=99.3:0.7. After mixing for 5 min the organic layer is separated the aqueous layer is extracted with isopropyl acetate (3×50.0 mL) The combined organic layers are washed with water (20.0 mL) concentrated under vacuum (20 mbar) until no further solvent distills