(S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate

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

Procedure: To tert-butyl (S)-1-((benzyloxy)carbonyl)-3-hydroxypropan-2-ylcarbamate (1 eq.) in dichloromethane was added 2,6-di-t-butyl 4-methylpyridine (2.5 eq.) and trimethyloxonium tetrafluoroborate (1.25 eq.) at 0° C. The reaction mixture was gradually warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane and washed with cold satd. sodium bicarbonate, water, and brine and dried over sodium sulfate. Purification by silica gel chromatography (25% EtOAc/Hexane) provide pure product as a colorless viscous liquid. washed with cold satd sodium bicarbonate, water, and brine and dried over sodium sulfate Purification by silica gel chromatography (25% EtOAc/Hexane) provide pure product as a colorless viscous liquid

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol (95.7 g) from Step 1 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate. the mixture was warmed to room temperature heated to 90° C. for 2 hours The mixture was cooled washed with 1N HCl (3×600 mL) The organic layer was washed with brine dried with sodium sulfate the solvents were removed in vacuo The residue was purified by chromatography on SiO2

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 mL) and the solution was cooled to −5° C. N-Methylmorpholine (10.32 mL) was added followed by a slow addition of isobutyl chloroformate (12.66 mL) such that the reaction temperature was kept below −10° C. The mixture was aged for 0.5 hour. The solids were quickly filtered and washed with dimethoxyethane (90 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C. Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The suspension was filtered, the solid washed with water (400 μL) and dried to yield benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate. was kept below −10° C The solids were quickly filtered washed with dimethoxyethane (90 mL) The filtrate was cooled to −50° C. a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C The suspension was filtered the solid washed with water (400 μL) dried

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 mL) and the solution was cooled to −5° C. N-Methylmorpholine (10.32 mL) was added followed by isobutyl chloroformate (12.7 mL) in such a way to keep the temperature below −10° C. The mixture was aged for 0.5 hour. The solids were quickly filtered and washed with dimethoxyethane (90 mL). To the filtrate cooled to −50° C. was carefully added sodium borohydride (4.4 g) as a solution in water (45 mL) in such a way to keep the temperature between −30° C. and −15° C. After all the hydride had been added, water (500 mL) was added in such a way to maintain the temperature below −15° C. The suspension was filtered, the solid washed with water (400 mL) and dried to yield benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate. the temperature below −10° C The solids were quickly filtered washed with dimethoxyethane (90 mL) To the filtrate cooled to −50° C. the temperature between −30° C. and −15° C After all the hydride had been added water (500 mL) was added in such a way to maintain the temperature below −15° C The suspension was filtered the solid washed with water (400 mL) dried

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Boc-L-aspartic acid-4-benzyl ester (100 g, 309 mmol) in DME (1.8 L) at −20° C. was added NMM (34 mL, 309 mmol) then dropwise iso-butylchloroformate (40 mL, 309 mmol) and the mixture was stirred at −20° C. for 20 min. The reaction mixture was filtered and the filtrate was cooled to −20° C. NaBH4 (17.5 g, 463 mmol) was added portionwise at −20° C. The mixture was allowed to warm and stirred at rt for 1 h. The mixture was quenched with a 20% citric acid solution and then extracted with AcOEt. The organic layer was washed with NaHCO3 solution, H2O and brine, dried (MgSO4), filtered and concentrated. The product was used without further purification for the next step. The reaction mixture was filtered to warm The mixture was quenched with a 20% citric acid solution extracted with AcOEt The organic layer was washed with NaHCO3 solution, H2O and brine dried (MgSO4) filtered concentrated The product was used without further purification for the next step

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

Procedure: To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)+; Rt-0.59 min. stirred for 1 hr The mixture was heated for 6 hr at 92° C. to cool to room temperature washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL) The organic layer was dried over sodium sulfate filtered off concentrated under reduced pressure The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25]

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

Procedure: To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)+; Rt-0.59 min. stirred for 1 hr The mixture was heated for 6 hr at 92° C. to cool to room temperature washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL) The organic layer was dried over sodium sulfate filtered off concentrated under reduced pressure The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25]

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol (95.7 g) from Step 7 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate. the mixture was warmed to room temperature heated to 90° C. for 2 hours The mixture was cooled washed with 1N HCl (3×600 mL) The organic layer was washed with brine dried with sodium sulfate the solvents were removed in vacuo The residue was purified by chromatography on SiO2

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol (95.7 g) from Step 7 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate. the mixture was warmed to room temperature heated to 90° C. for 2 hours The mixture was cooled washed with 1N HCl (3×600 mL) The organic layer was washed with brine dried with sodium sulfate the solvents were removed in vacuo The residue was purified by chromatography on SiO2

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol (95.7 g) from Step 7 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate. the mixture was warmed to room temperature heated to 90° C. for 2 hours The mixture was cooled washed with 1N HCl (3×600 mL) The organic layer was washed with brine dried with sodium sulfate the solvents were removed in vacuo The residue was purified by chromatography on SiO2

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(tert-Butoxycarbonyl)-L-aspartic acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 mL) and the solution was cooled to −5° C. N-Methylmorpholine (10.32 mL) was added followed by a slow addition of isobutyl chloroformate (12.66 mL) such that the reaction temperature was kept below −10° C. The mixture was aged for 0.5 hour. The solids were quickly filtered and washed with dimethoxyethane (90 mL). The filtrate was cooled to −50° C. and a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C. Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C. The suspension was filtered, the solid washed with water (400 mL) and dried to yield benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoate. was kept below −10° C The solids were quickly filtered washed with dimethoxyethane (90 mL) The filtrate was cooled to −50° C. a solution of sodium borohydride (4.4 g) in water (45 mL) was added slowly such that the reaction temperature was maintained between −30° C. and −15° C Water (500 mL) was then added such that the reaction mixture temperature was maintained below −15° C The suspension was filtered the solid washed with water (400 mL) dried

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the alcohol (95.7 g) from Step 1 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate. the mixture was warmed to room temperature heated to 90° C. for 2 hours The mixture was cooled washed with 1N HCl (3×600 mL) The organic layer was washed with brine dried with sodium sulfate the solvents were removed in vacuo The residue was purified by chromatography on SiO2