N-(4-bromophenyl)formamide

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: To a stirred 2M solution of borane methyl sulfide complex in THF (580 mL, 1.16 mol) at 0° C. was slowly added a solution of N-(4-bromo-phenyl)-formamide (Example 1, Step (1), 93 g., 0.465 mol) in 280 mL of THF so that the temperature of the solution did not rise above 5° C. Once the addition of the formanilide was complete, the reaction was brought to reflux and stirred for 3 hours. The reaction was then cooled to 0° C. and 190 mL of methanol was added slowly to control the frothing of the reaction. Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2. The solvents were removed in vacuo to afford a solid. The solid was dissolved in water and the pH was raised to 10, and the solution was extracted twice with ethyl ether. The combined ether extracts were washed twice with brine and dried over sodium sulfate. Removal of the ether solvent afforded 85.5 grams (98.8%) of (4-bromo-phenyl)-methyl-amine. The spectral properties of the oil were consistent with the desired material. High performance liquid chromatography (“HPLC”) analysis revealed that the oil was greater than 95% of 4-bromophenyl-N-methylaniline. This material was used in the next step without purification. Step (3): 7-Bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l6-benzo[1,2,4]thiadiazin-3-one did not rise above 5° C to reflux the frothing of the reaction Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2 The solvents were removed in vacuo to afford a solid the pH was raised to 10 the solution was extracted twice with ethyl ether The combined ether extracts were washed twice with brine dried over sodium sulfate Removal of the ether solvent

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

実験手順: A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine the temperature of the reaction mixture above 10° C the temperature of the reaction was raised to 50-60° C. The reaction was then cooled to 0° C. After the addition to stir at this temperature for 4 hours The reaction mixture was transferred to a round bottom flask the solvent was removed in vacuo When the solvent had been removed the residue crystallized The solid was triturated with heptane filtered

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: To a stirred 2M solution of borane methyl sulfide complex in THF (580 mL, 1.16 mol) at 0° C. was slowly added a solution of N-(4-bromo-phenyl)-formamide (Example 1, Step (1), 93 g., 0.465 mol) in 280 mL of THF so that the temperature of the solution did not rise above 5° C. Once the addition of the formanilide was complete, the reaction was brought to reflux and stirred for 3 hours. The reaction was then cooled to 0° C. and 190 mL of methanol was added slowly to control the frothing of the reaction. Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2. The solvents were removed in vacuo to afford a solid. The solid was dissolved in water and the pH was raised to 10, and the solution was extracted twice with ethyl ether. The combined ether extracts were washed twice with brine and dried over sodium sulfate. Removal of the ether solvent afforded 85.5 grams (98.8%) of (4-bromo-phenyl)-methyl-amine. The spectral properties of the oil were consistent with the desired material. High performance liquid chromatography (“HPLC”) analysis revealed that the oil was greater than 95% of 4-bromophenyl-N-methylaniline. This material was used in the next step without purification. Step (3): 7-Bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l6-benzo[1,2,4]thiadiazin-3-one did not rise above 5° C to reflux the frothing of the reaction Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2 The solvents were removed in vacuo to afford a solid the pH was raised to 10 the solution was extracted twice with ethyl ether The combined ether extracts were washed twice with brine dried over sodium sulfate Removal of the ether solvent

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

実験手順: A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine the temperature of the reaction mixture above 10° C the temperature of the reaction was raised to 50-60° C. The reaction was then cooled to 0° C. After the addition to stir at this temperature for 4 hours The reaction mixture was transferred to a round bottom flask the solvent was removed in vacuo When the solvent had been removed the residue crystallized The solid was triturated with heptane filtered

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

実験手順: A solution of N-(4-bromophenyl)-formamide 50 (250 mg, 1.25 mmol) in DMF (3 mL) is added dropwise to a suspension of sodium hydride (65 mg, 1.63 mmol, 60% dispersion in mineral oil) in DMF (3 mL) at 0° C. After stirring 1 h, iodomethane (113 μl, 1.63 mmol) is added, the reaction mixture warmed to RT and stirred 16 h. The reaction is then quenched with water (10 mL) and extracted into EtOAc (3×10 mL). The combined organic phases are dried over Na2SO4 and reduced in vacuo to give the title compound. stirred 16 h The reaction is then quenched with water (10 mL) extracted into EtOAc (3×10 mL) The combined organic phases are dried over Na2SO4

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

実験手順: A stirred solution of formic acid (2.5 mL, 88% in water) is cooled to 0° C., treated with acetic anhydride (0.82 mL, 9.0 mmol) then warmed to RT over 30 minutes. The solution is then cooled to 0° C. and 4-bromoaniline (500 mg, 3.0 mmol) added dropwise over 5 minutes. After stirring a further 16 h at RT, the reaction mixture is diluted with water (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with 1 M HCl (20 mL) and aqueous NaHCO3 (20 mL), dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (20% EtOAc in heptane) affords the title compound. The solution is then cooled to 0° C. extracted into DCM (3×20 mL) The combined DCM phases are washed with 1 M HCl (20 mL) and aqueous NaHCO3 (20 mL) dried over Na2SO4 Purification by column chromatography (20% EtOAc in heptane)

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

実験手順: To a solution of N-(4-Bromo-phenyl)-formamide D32a (8.2 g, 41 mmol) in dry THF (100 mL) was added BF3.Et2O (8.2 mL, 61 mmol). The mixture was heated to reflux and BH3. THF (103 mL, 103 mmol) added dropwise, the mixture was heated for a further 2 hours. After cooling to room temperature concentrated HCl (100 mL) was added and the mixture stirred for one hour. The pH of the mixture was adjusted to pH 13 using concentrated NaOH. Extraction with ether, drying over MgSO4 and evaporating to dryness gave the subtitled compound as light brown oil (7.58 g). MH+ 186/188. 1H NMR δ (CDCl3) 2.81 (3H, s), 3.63-3.78 (1H, br.s), 6.43-6.52 (2H, d), 7.22-7.30 (2H, d). The mixture was heated to reflux the mixture was heated for a further 2 hours was added Extraction with ether drying over MgSO4 evaporating to dryness

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

実験手順: Formic acid (7 mL, 186 mmol) and acetic anhydride (140.1 mL, 150 mmol) were heated together at 55° C. for 2 hours. The mixture was cooled to room temperature, THF (11 mL) was added followed by 4-bromoaniline (10 g, 58 mmol) in THF (20 mL). The mixture was stirred at room temperature for 3 hours before evaporating to dryness. Trituration of the solid gave the subtitled compound as a light brown solid (8.22 g). MH− 198/200. 1H NMR δ (CDCl3) 6.93-7.04 (2H, d), 7.24 (2H, s), 8.59-8.70 (1H, d). before evaporating to dryness

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

実験手順: To a stirred 2M solution of borane methyl sulfide complex in THF (580 mL, 1.16 mol) at 0° C. was slowly added a solution of N-(4-bromo-phenyl)-formamide (Example 1, Step (1), 93 g., 0.465 mol) in 280 mL of THF so that the temperature of the solution did not rise above 5° C. Once the addition of the formanilide was complete, the reaction was brought to reflux and stirred for 3 hours. The reaction was then cooled to 0° C. and 190 mL of methanol was added slowly to control the frothing of the reaction. Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2. The solvents were removed in vacuo to afford a solid. The solid was dissolved in water and the pH was raised to 10, and the solution was extracted twice with ethyl ether. The combined ether extracts were washed twice with brine and dried over sodium sulfate. Removal of the ether solvent afforded 85.5 grams (98.8%) of (4-bromo-phenyl)-methyl-amine. The spectral properties of the oil were consistent with the desired material. High performance liquid chromatography (“HPLC”) analysis revealed that the oil was greater than 95% of 4-bromophenyl-N-methylaniline. This material was used in the next step without purification. Step (3): 7-Bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l6-benzo[1,2,4]thiadiazin-3-one did not rise above 5° C to reflux the frothing of the reaction Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2 The solvents were removed in vacuo to afford a solid the pH was raised to 10 the solution was extracted twice with ethyl ether The combined ether extracts were washed twice with brine dried over sodium sulfate Removal of the ether solvent

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

実験手順: A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine the temperature of the reaction mixture above 10° C the temperature of the reaction was raised to 50-60° C. The reaction was then cooled to 0° C. After the addition to stir at this temperature for 4 hours The reaction mixture was transferred to a round bottom flask the solvent was removed in vacuo When the solvent had been removed the residue crystallized The solid was triturated with heptane filtered