4-fluoro-N-methylbenzamide

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

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

Procedure: This compound was prepared from 4-Fluoro-N-methylbenzylamine which in turn was prepared from 4-Fluoro-N-methylbenzamide. Practical details are as follows: 4-Fluorobenzoyl chloride (25g) was added dropwise to a stirred aqueous solution of methylamine (40% w/v; 250 ml) at 0° C. over 30 min. The mixture was stirred for 12 h at room temperature, concentrated to half volume and the resulting crystalline precipitate was collected and recrystallized from water to furnish the N-methylbenzamide as colourless needles, (24.1 g; 89.1%), m.p. 131°-132° C. concentrated to half volume the resulting crystalline precipitate was collected recrystallized from water

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

Procedure: This compound was prepared from 4-Fluoro-N-methylbenzylamine which in turn was prepared from 4-Fluoro-N-methylbenzamide. Practical details are as follows: 4-Fluorobenzoyl chloride (25g) was added dropwise to a stirred aqueous solution of methylamine (40% w/v; 250 ml) at 0° C. over 30 min. The mixture was stirred for 12 h at room temperature, concentrated to half volume and the resulting crystalline precipitate was collected and recrystallized from water to furnish the N-methylbenzamide as colourless needles, (24.1 g; 89.1%), m.p. 131°-132° C. concentrated to half volume the resulting crystalline precipitate was collected recrystallized from water

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to 40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fritted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1 H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to 40° C. filtered rinsed with warm H2O (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fritted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3H) 2.77-2.86 (m, 4H) 3.08-3.18 (m, 4H) 6.91 (m, 2H) 7.69 (m, 2H) 8.13 (q, J=4.04 Hz, 1H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (˜50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to ˜40° C. filtered rinsed with warm H2O (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fitted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to 40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fritted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1 H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to 40° C. filtered rinsed with warm H2O (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fritted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to 40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fritted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1 H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to 40° C. filtered rinsed with warm H2O (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fritted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo

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

Procedure: To a stirred solution of 4-fluorobenzoic acid (200 mg, 1.43 mmol) in DCE (3 ml) at RT, was added a solution of methyl amine in THF (2 M, 1.43 mmol) and NEt3 (198 μl, 1.43 mmol) and allowed to stir for ca. 10 mins. HOBt (221 mg, 1.43 mmol) and DCC (295 mg, 1.43 mmol) were added and the reaction mixture heated at 70° C. for 3 h. After cooling to RT, the reaction mixture was washed with sat. NaHCO3 (5 ml) and the aqueous back extracted with DCM. The organics were combined, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH gradient 100:0 to 80:20) provided the title compound as off-white solid (137 mg, 63%). After cooling to RT the reaction mixture was washed with sat. NaHCO3 (5 ml) the aqueous back extracted with DCM dried (MgSO4) filtered concentrated under reduced pressure Purification by silica flash column chromatography (eluting with DCM/MeOH gradient 100:0 to 80:20)

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

Procedure: To a solution of 30 mL MeNH2 (40% wt in H2O) was added 139 mL of 1N NaOH. To this was added 130 mL of CH2Cl2 followed by 4-fluorobenzoyl chloride (22 grams, 139 mmol) while the mixture was rapidly stirred. After 1 hour the organic layer was separated, washed with H2O, dried over Na2SO4 and solvent removed under vacuum to yield 20 grams (94% yield) solid. 1H NMR (500 MHz, DMSO) δ: 2.78 (d, 3, J=5), 7.28 (t, 2, J=9), 7.91 (m, 2), 8.46 (br s, 1). 13C NMR (125 MHz, DMSO) δ: 26.13, 114.95, 115.13, 129.49, 129.56, 130.87, 130.90, 162.67, 164.64, 165.46. After 1 hour the organic layer was separated washed with H2O dried over Na2SO4 and solvent removed under vacuum

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H20 (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (˜50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to ˜40° C. filtered rinsed with warm H20 (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fitted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H20 (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3H) 2.77-2.86 (m, 4H) 3.08-3.18 (m, 4H) 6.91 (m, 2H) 7.69 (m, 2H) 8.13 (q, J=4.04 Hz, 1H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C. the reaction vessel was rinsed with H2O (˜50 mL) Next, celite (30 g) was added the filtration The resulting suspension was warmed to 100° C. cooled to ˜40° C. filtered rinsed with warm H20 (4×50 mL) The resulting solid was dried in vacuo The filtrate was stirred at room temperature overnight affording a suspension The suspension was filtered rinsed with H2O (3×25 mL) the resulting solid was dried in vacuo The cloudy filtrate was filtered once again through a medium fitted funnel rinsed with H2O (3×10 mL) Added NaCl (200.1 g) to the filtrate, cooled on ice filtered rinsed with cold H2O (3×25 mL) dried the resulting solid in vacuo Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C. filtered rinsed with H2O (3×5 mL) dried the resulting solid in vacuo agitated for 10 min dried in vacuo