N-methoxy-N-methylpiperidine-4-carboxamide

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:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of N-methoxy-N-methylpiperidine-4-carboxamide (40 g, 232 mmol) in acetone (400 mL) was added benzyl bromide (42 mL, 349 mmol) and K2CO3 (64 g, 465 mmol) and the reaction mixture was stirred at 80° C. under reflux for 16 h. After completion of the reaction, the reaction mixture was filtered and acetone was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane) to afford 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=263.15 under reflux for 16 h After completion of the reaction the reaction mixture was filtered acetone was removed under reduced pressure The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane)

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) in DCM (400 mL) was added trifluoroacetic acid (150 mL) and the resulting mixture was stirred for 6 h at 25-30° C. After completion of the reaction, the solvent was removed under reduced pressure to afford 40 g of N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04 After completion of the reaction the solvent was removed under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of N-methoxy-N-methylpiperidine-4-carboxamide (40 g, 232 mmol) in acetone (400 mL) was added benzyl bromide (42 mL, 349 mmol) and K2CO3 (64 g, 465 mmol) and the reaction mixture was stirred at 80° C. under reflux for 16 h. After completion of the reaction, the reaction mixture was filtered and acetone was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane) to afford 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=263.15 under reflux for 16 h After completion of the reaction the reaction mixture was filtered acetone was removed under reduced pressure The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane)

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) in DCM (400 mL) was added trifluoroacetic acid (150 mL) and the resulting mixture was stirred for 6 h at 25-30° C. After completion of the reaction, the solvent was removed under reduced pressure to afford 40 g of N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04 After completion of the reaction the solvent was removed under reduced pressure

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) in DCM (400 mL) was added trifluoroacetic acid (150 mL) and the resulting mixture was stirred for 6 h at 25-30° C. After completion of the reaction, the solvent was removed under reduced pressure to afford 40 g of N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04 After completion of the reaction the solvent was removed under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask containing 2-(2′-di-tent-butylphosphine)biphenylpalladium(II) acetate (0.927 g, 2.003 mmol) and potassium tert-butoxide (1.798 g, 16.03 mmol) was flushed with nitrogen and then charged with 4-bromochlorobenzene (3.07 g, 16.03 mmol), N-methoxy-N-methylpiperidine-4-carboxamide (2.3 g, 13.35 mmol) and anhydrous toluene (25 mL). The resulting mixture was stirred under nitrogen at 100° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature, diluted with ether (200 mL), washed with water and brine, dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and an eluent gradient from 10:1 Hex/EtOAc to 2:1 EtOAc/Hex. The fractions containing the product were pooled and concentrated on a rotary evaporator to the title compound (2.2 g, 7.78 mmol, 58.3% yield) as a yellow-green solid. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm). 283.19, [M+H]; tR=1.79 min; 4 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate. 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.21 (2H, m), 6.81-6.87 (2H, m), 3.72 (3H, s), 3.69 (1H, t, J=3.30 Hz), 3.66 (1H, t, J=2.86 Hz), 3.19 (3H, s), 2.70-2.82 (3H, m), 1.82-1.94 (4H, m). was flushed with nitrogen After this time, the reaction mixture was cooled to room temperature washed with water and brine dried over MgSO4 concentrated to yield a residue The residue was purified by flash chromatography The fractions containing the product

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask containing 2-(2′-di-tent-butylphosphine)biphenylpalladium(II) acetate (0.927 g, 2.003 mmol) and potassium tert-butoxide (1.798 g, 16.03 mmol) was flushed with nitrogen and then charged with 4-bromochlorobenzene (3.07 g, 16.03 mmol), N-methoxy-N-methylpiperidine-4-carboxamide (2.3 g, 13.35 mmol) and anhydrous toluene (25 mL). The resulting mixture was stirred under nitrogen at 100° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature, diluted with ether (200 mL), washed with water and brine, dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and an eluent gradient from 10:1 Hex/EtOAc to 2:1 EtOAc/Hex. The fractions containing the product were pooled and concentrated on a rotary evaporator to the title compound (2.2 g, 7.78 mmol, 58.3% yield) as a yellow-green solid. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm). 283.19, [M+H]; tR=1.79 min; 4 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate. 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.21 (2H, m), 6.81-6.87 (2H, m), 3.72 (3H, s), 3.69 (1H, t, J=3.30 Hz), 3.66 (1H, t, J=2.86 Hz), 3.19 (3H, s), 2.70-2.82 (3H, m), 1.82-1.94 (4H, m). was flushed with nitrogen After this time, the reaction mixture was cooled to room temperature washed with water and brine dried over MgSO4 concentrated to yield a residue The residue was purified by flash chromatography The fractions containing the product

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

Procedure: A solution of benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.0 g, 16.32 mmol) in absolute EtOH (75 mL) was charged with 10% Pd-carbon (500 mg). The flask was evacuated and backfilled with hydrogen. The mixture was stirred for 60 h under 1 atmosphere of hydrogen (latex balloon). The catalyst was removed by filtration and the filtrate concentrated and azeotroped twice with MeOH (50 mL) to give the title compound (2.6 g, 15.10 mmol, 92% yield) as a pale yellow oil. LC-MS: (Waters Sunfire C18 4.6 mm×30 mm). 313.20, [M+H]; tR=0.12 min; 2 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 5 mL/min flow rate. 1H-NMR (400 MHz, CDCl3) δ ppm 3.65 (3H, s), 3.12 (3H, s), 3.08 (2H, dt, J=12.59, 3.27 Hz), 2.76 (1H, s), 2.61 (2H, td, J=12.21, 3.27 Hz), 1.57-1.69 (5H, m). The flask was evacuated The catalyst was removed by filtration the filtrate concentrated azeotroped twice with MeOH (50 mL)

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