tert-butyl 3-oxo-2-phenylpiperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (−70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at −70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at −70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 m), 2.0 (2H, m), and 1.54 (9H, s). The mixture was stirred at −70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)

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

Procedure: A tetrahydrofluran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91M, 3 ml) (Louw et. al. Tetrahedron 48:6087-6104, (1992), prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (±)1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc. 1) in tetrahydrofuran (3 ml). The solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%). Evaporation of the fractions gave the title compound. m/z (CI+)424 (M+H), 324 (M+2H--t-BuOCO--), 368 (M+2H--t-Bu). quenched by addition of saturated ammonium chloride solution (20 ml) extracted with ethyl acetate (20 ml) The organic phase was washed (saturated brine) dried (MgSO4) evaporated to a small volume purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%) Evaporation of the fractions

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (-60° C.) solution of oxalyl chloride (0.68 ml, 7.8 mmol) in dichloronmethane (17 ml) was added dimethyl sulphoxide (0.69 ml, 9.8 mmol) for 10 minutes before addition of (±)1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (1.8 g, 6.5 mmol; prepared by the method described in European Patent Specification number 0 528 495-A) in dichloromethane (7 ml). The solution was stirred at -60° C. for 20 minutes, warmed to -30° C. and triethylamine (2.5 ml) added. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40 ml, twice), water and dried (MgSO4). After evaporation the residue was purified by chromatography on silica gel (eluting with hexane containing an increasing proportion of ethyl acetate up to 20%) to give the title compound. prepared by the method warmed to -30° C. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40 ml twice), water and dried (MgSO4) After evaporation the residue was purified by chromatography on silica gel ( eluting with hexane containing an increasing proportion of ethyl acetate up to 20%)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (-60° C.) solution of oxalyl chloride (0.68 ml, 7.8 mmol) in dichloronmethane (17 ml) was added dimethyl sulphoxide (0.69 ml, 9.8 mmol) for 10 minutes before addition of (±)1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (1.8 g, 6.5 mmol; prepared by the method described in European Patent Specification number 0 528 495-A) in dichloromethane (7 ml). The solution was stirred at -60° C. for 20 minutes, warmed to -30° C. and triethylamine (2.5 ml) added. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40 ml, twice), water and dried (MgSO4). After evaporation the residue was purified by chromatography on silica gel (eluting with hexane containing an increasing proportion of ethyl acetate up to 20%) to give the title compound. prepared by the method warmed to -30° C. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40 ml twice), water and dried (MgSO4) After evaporation the residue was purified by chromatography on silica gel ( eluting with hexane containing an increasing proportion of ethyl acetate up to 20%)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 9.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (−70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at −70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at −70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3)δ7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s). The mixture was stirred at −70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s). The mixture was stirred at -70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s). The mixture was stirred at -70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ7.5-7.3 (5 H, m), 5.8 (1 H, br s), 4.2 (1 H, br s), 3.4 (1 H, m), 2.6 (2 H, m), 2.0 (2 H, m), and 1.54 (9 H, s). The mixture was stirred at -70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s). The mixture was stirred at -70° C. for 1 h. The mixture was stirred at room temperature for 1 h. the mixture was stirred at room temperature overnight The layers were separated the aqueous layer was extracted with dichloromethane (2×300 mL) The combined organic fractions were washed with brine dried (MgSO4) the solvent was evaporated under reduced pressure The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10)