4-methoxy-4-methylpiperidine

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

Procedure: O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409). the resulting solution was stirred at 25° C. for 4 hours The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%) m/z (LC-MS, ESI+), RT=1.79 (M+H 409)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409). the resulting solution was stirred at 25° C. for 4 hours The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%) m/z (LC-MS, ESI+), RT=1.79 (M+H 409)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoroacetic acid (2.54 mL, 32.97 mmol) was added dropwise to tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate (22) (756 mg, 3.30 mmol) in dichloromethane (10 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 15 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the desired compound as an oil (235 mg, 55.2%); 1H NMR (400.132 MHz, CDCl3) δ 1.15 (3H, s), 1.41-1.49 (2H, m), 1.68-1.74 (2H, m), 2.76 (2H, dt), 2.93 (2H, dt), 3.19 (3H, s), 3.49 (1H, s). The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness

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

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

Procedure: A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol), triethylamine (0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine (0.45 g, 3.49 mmol)in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (0.50 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.45-7.39 (m, 2H), 7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H), 2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s, 3H). The solvent was evaporated the resultant residue was diluted with saturated aqueous sodium bicarbonate solution extracted with ethyl acetate (2×50 mL) The combined organic layer was dried over sodium sulfate filtered evaporated

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

Procedure: A solution of 20.1 g (0.1 m) of gamma-chloro-p-fluorobutyrophenone, 30 g (0.2 m) of 4-methyl-4-methoxy-piperidine and 0.1 g. of potassium iodide in 150 ml of toluene is heated in a glass autoclave for 15 hours at 100°-110° C. The KI and the 4-methyl-4-methoxy-piperidine hydrochloride formed in the reaction are separated by filtration and the solvent removed from the filtrate by evaporation under a vacuum on a steam bath. The obtained base is dissolved in ether and the hydrochloride is precipitated with alcoholic HCl. The reaction product is purified by recrystallization from ethanol-ether. Yield 22 g. Melting point 182° C.

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

Procedure: A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol), triethylamine (0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine (0.45 g, 3.49 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a yellow oil (0.50 g, 96%). 1H NMR (CDCl3, 300 MHz): 7.45-7.39 (m, 2H), 7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H), 2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s, 3H). The solvent was evaporated the resultant residue was diluted with saturated aqueous sodium bicarbonate solution extracted with ethyl acetate (2×50 mL) The combined organic layer was dried over sodium sulfate filtered evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409). the resulting solution was stirred at 25° C. for 4 hours The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%) m/z (LC-MS, ESI+), RT=1.79 (M+H 409)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoroacetic acid (2.54 mL, 32.97 mmol) was added dropwise to tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate (22) (756 mg, 3.30 mmol) in dichloromethane (10 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 15 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the desired compound as an oil (235 mg, 55.2%); 1H NMR (400.132 MHz, CDCl3) δ 1.15 (3H, s), 1.41-1.49 (2H, m), 1.68-1.74 (2H, m), 2.76 (2H, dt), 2.93 (2H, dt), 3.19 (3H, s), 3.49 (1H, s). The crude product was purified by ion exchange chromatography The desired product was eluted from the column were evaporated to dryness