benzyl 2-bromo-2-methylpropanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Bromo-2-methylpropionyl bromide (6.8 mL) was diluted with dichloromethane and added to a solution of triethylamine (7.7 mL) and benzyl alcohol (4.8 mL), while the mixture was cooled in an ice bath and while maintaining an argon atmosphere. The solution was stirred for one hour at 0° C. and then overnight at room temperature. Volatiles were evaporated and the residue was treated with diethylether. The formed salt was removed by filtration and the filtrate was washed with an HCl solution and with water. The ether solution was dried with MgSO4 and concentrated to yield a yellowish liquid. Silica column chromatography using a 2/1 hexane/ethyl acetate mixture as eluent gave a colourless transparent liquid. 1H NMR (400 MHz, CDCl3): δ 7.4 (5H), 5.3 (2H), 2.0 (6H). was cooled in an ice bath while maintaining an argon atmosphere overnight at room temperature Volatiles were evaporated the residue was treated with diethylether The formed salt was removed by filtration the filtrate was washed with an HCl solution and with water The ether solution was dried with MgSO4 concentrated to yield a yellowish liquid gave a colourless transparent liquid

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m). was sonicated for 6 h The reaction was quenched with sat. NaHCO3 extracted with ether concentrated The residue was purified by silica gel flash chromatography

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

実験手順: A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m). was sonicated for 6 h The reaction was quenched with sat. NaHCO3 extracted with ether concentrated The residue was purified by silica gel flash chromatography

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 4,4-difluoropiperidine/HCl (158 mg), benzyl 2-bromo-2-methylpropanoate (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL) in a capped vial was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ether, washed with satd. NaHCO3, water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate as a viscous oil (33.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.46 (5H, m), 5.18 (2H, s), 2.66 (4H, t, J=5.40 Hz), 1.86-2.08 (4H, m), 1.36 (6H, s). Benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate was debenzylated by hydrogenation (10% Pd/C, EtOAc) to afford Cap P-16 as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s). The reaction mixture was evaporated to dryness the residue was dissolved in ether washed with satd NaHCO3, water, brine and dried (MgSO4) The crude product was purified by silica gel FCC (0-1% MeOH in DCM)

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 4,4-difluoropiperidine/HCl (158 mg), benzyl 2-bromo-2-methylpropanoate (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL) in a capped vial was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ether, washed with satd. NaHCO3, water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate as a viscous oil (33.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.46 (5H, m), 5.18 (2H, s), 2.66 (4H, t, J=5.40 Hz), 1.86-2.08 (4H, m), 1.36 (6H, s). Benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate was debenzylated by hydrogenation (10% Pd/C, EtOAc) to afford Cap P-16 as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s). The reaction mixture was evaporated to dryness the residue was dissolved in ether washed with satd NaHCO3, water, brine and dried (MgSO4) The crude product was purified by silica gel FCC (0-1% MeOH in DCM)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Bromo-2-methylpropionyl bromide (6.8 mL) was diluted with dichloromethane and added to a solution of triethylamine (7.7 mL) and benzyl alcohol (4.8 mL), while the mixture was cooled in an ice bath and while maintaining an argon atmosphere. The solution was stirred for one hour at 0° C. and then overnight at room temperature. Volatiles were evaporated and the residue was treated with diethylether. The formed salt was removed by filtration and the filtrate was washed with an HCl solution and with water. The ether solution was dried with MgSO4 and concentrated to yield a yellowish liquid. Silica column chromatography using a 2/1 hexane/ethyl acetate mixture as eluent gave a colourless transparent liquid. 1H NMR (400 MHz, CDCl3): δ 7.4 (5H), 5.3 (2H), 2.0 (6H). was cooled in an ice bath while maintaining an argon atmosphere overnight at room temperature Volatiles were evaporated the residue was treated with diethylether The formed salt was removed by filtration the filtrate was washed with an HCl solution and with water The ether solution was dried with MgSO4 concentrated to yield a yellowish liquid gave a colourless transparent liquid

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (554 mgs, 2.4 mmol) in CH3CN (5 mL) and K2CO3 (1.1 g, 8.0 mmol) was added benzyl 2-bromo-2-methylpropanoate (512 mgs, 2.0 mmol). The reaction mixture was heated to 80° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, stirred and filtered. The filtrate was then concentrated and purified by flash chromatography on silica gel with elution using 3% MeOH/CH2Cl2 to give Benzyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propanoate. the reaction mixture was cooled to room temperature filtered The filtrate was then concentrated purified by flash chromatography on silica gel with elution

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (554 mgs, 2.4 mmol) in CH3CN (5 mL) and K2CO3 (1.1 g, 8.0 mmol) was added benzyl 2-bromo-2-methylpropanoate (512 mgs, 2.0 mmol). The reaction mixture was heated to 80° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, stirred and filtered. The filtrate was then concentrated and purified by flash chromatography on silica gel with elution using 3% MeOH/CH2Cl2 to give Benzyl 2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propanoate. the reaction mixture was cooled to room temperature filtered The filtrate was then concentrated purified by flash chromatography on silica gel with elution

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

実験手順: A stirred suspension of benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pyran-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) in THF (3 mL) was sonicated for 6 h. The reaction was quenched with sat. NaHCO3 and extracted with ether, then concentrated. The residue was purified by silica gel flash chromatography to afford benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.43 (5H, m), 5.18 (2H, s), 3.51-3.61 (2H, m), 2.41 (2H, t, J=7.10 Hz), 1.56-1.66 (2H, m), 1.35-1.47 (8H, m). Benzyl 2-(2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate was dissolved in triethylsilane (0.415 mL, 2.60 mmol) and treated with TFA (0.200 mL, 2.60 mmol) and the reaction mixture was stirred at rt for 16 h, then evaporated to dryness to yield benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.30-7.41 (5H, m), 5.22 (1H, d, J=12.66 Hz), 5.10 (1H, d, J=12.51 Hz), 3.91-4.01 (1H, m), 3.53 (1H, dd, J=11.22, 1.75 Hz), 3.39 (1H, td, J=11.56, 2.37 Hz), 1.82-1.92 (1H, m), 1.44-1.59 (4H, m), 1.30-1.41 (1H, m), 1.19-1.25 (3H, m), 1.11-1.19 (3H, m). A stirred suspension of 10% Pd—C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) in EtOAc (5 mL) was stirred under H2 for 6 h, and then filtered and concentrated to yield Cap P-23 (54 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.09-4.19 (1H, m), 3.48-3.57 (1H, m), 3.33-3.42 (1H, m), 1.88-1.97 (1H, m), 1.71 (1H, d, J=13.12 Hz), 1.47-1.65 (3H, m), 1.29-1.40 (1H, m), 1.23-1.27 (3H, m), 1.14-1.20 (3H, m). was sonicated for 6 h The reaction was quenched with sat. NaHCO3 extracted with ether concentrated The residue was purified by silica gel flash chromatography