4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

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:0.00; pressure:0.00; stir:

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

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

Procedure: To a solution of 2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g, 177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mL of concentrated HCl. The reaction mixture was hydrogenated using a hydrogen balloon for 22 h. The solution was filtered through celite and concentrated to a minimum volume, after which solid was filtered, washed with ether. The filtrate concentrated again and trituated with EtOH and repeated several times to get out more products. The solid was combined and further dried to give total 50 g of product as light yellow powder (>98%). 1H NMR (400 MHz, DMSO-d6) δ 1.64-2.02 (m, 4H) 2.61 (s, 3H) 2.90 (t, J=11.0 Hz, 2H) 3.24 (m, 2H) 3.72-3.81 (m, 3H) 3.84-4.03 (m, 1H) 5.60 (s, 2H) 6.29-6.50 (m, 1H) 7.01 (d, J=6.8 Hz, 1H) 7.69 (dd, J=7.3, 4.8 Hz, 1H). [M+H] calc'd for C14H20FN3O2, 282. found 282. for 22 h The solution was filtered through celite concentrated to a minimum volume after which solid was filtered washed with ether The filtrate concentrated again to get out more products further dried

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

Procedure: 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H) 1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br. d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd, J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd for C25H32F3N7O3, 536. found 536. cooled stirred for 5 min The precipitate was filtered washed with water (5 mL) dried in air for 20-30 min treated with solid sodium bicarbonate (130 mg) stirred vigorously for 45 min The insoluble salts were filtered off filtrate was concentrated in vacuo The residue was crystallized from ethanol-water (1:7; 8 mL) dried in vacuum

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

Procedure: 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H) 1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br. d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd, J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd for C25H32F3N7O3, 536. found 536. cooled stirred for 5 min The precipitate was filtered washed with water (5 mL) dried in air for 20-30 min treated with solid sodium bicarbonate (130 mg) stirred vigorously for 45 min The insoluble salts were filtered off filtrate was concentrated in vacuo The residue was crystallized from ethanol-water (1:7; 8 mL) dried in vacuum

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

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

Procedure: 2-fluoro-5-methoxy-N-(1-methyl-4-piperidyl)-4-nitro-benzamide Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 25° C. under Hydrogen at 1 bar pressure for 18 hours.

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

Procedure: 2-fluoro-5-methoxy-N-(1-methyl-4-piperidyl)-4-nitro-benzamide Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 25° C. under Hydrogen at 1 bar pressure for 18 hours.

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

Procedure: 2-fluoro-5-methoxy-N-(1-methyl-4-piperidyl)-4-nitro-benzamide Intermediate 28; 1.3 g, 4.2 mmol) 10% Palladium on Carbon (100 mg) and Methanol (50 mL) were combined and stirred at 25° C. under Hydrogen at 1 bar pressure for 18 hours.