2,6-dichloro-4-fluoroaniline

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4-fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite®. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification. warmed to room temperature stirred for a further 4 hours The mixture was concentrated under reduced pressure The residue was dissolved in toluene filtered through Celite® The filtrate was concentrated under to dryness under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.0 g, 6.75 mmol), 2,6-dichloro-4-fluorophenylamine (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0° C., warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis. a cooled warmed to room temperature stirred for an additional 2 h concentrated under reduced pressure The residue was dissolved in toluene filtered though a pad of Celite® The filtrate was concentrated to dryness under reduced pressure

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 0° C. solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0° C. for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96%). LC-ES/MS m/e 194.0 (M+1) The ice bath is removed the reaction is stirred for 18 h The reaction is filtered the solid is washed with isopropyl alcohol The solid is dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 0° C. solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0° C. for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96%). LC-ES/MS m/e 194.0 (M+1) The ice bath is removed the reaction is stirred for 18 h The reaction is filtered the solid is washed with isopropyl alcohol The solid is dried

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

Procedure: 9.0 g (0.05 mol) of 2,6-dichloro-4-fluoroaniline was added to 50 ml of concentrated hydrochloric acid, and a solution of 3.8 g (0.055 mol) of sodium nitrite in 25 ml of water was dropwise added thereto at a temperature of from 0° to 5° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 1 hour. Insolubles were removed by filtration, and the filtrate was dropwise added at a temperature of from 0° to 10° C. to a solution of 33.8 g (0.15 mol) of stannous chloride dihydrate in 50 ml of concentrated hydrochloric acid. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 2 hours. The precipitated hydrochloride was collected by filtration, and 50 ml of water was added thereto. The mixture was made alkaline with an addition of 20% sodium hydroxide, and the precipitated solid was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue thereby obtained was washed with cold n-hexane to obtain 6.9 g (yield: 70.4%) of the desired compound as white feather-like crystals. Melting point: 117°-119° C. of from 0° to 5° C After completion of the dropwise addition Insolubles were removed by filtration After completion of the dropwise addition the mixture was stirred at the same temperature for further 2 hours The precipitated hydrochloride was collected by filtration, and 50 ml of water was added with an addition of 20% sodium hydroxide the precipitated solid was extracted with ethyl ether The ethyl ether layer was washed with water dried over anhydrous sodium sulfate Then, the solvent was distilled off The residue thereby obtained was washed with cold n-hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4-fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite®. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification. warmed to room temperature stirred for a further 4 hours The mixture was concentrated under reduced pressure The residue was dissolved in toluene filtered through Celite® The filtrate was concentrated under to dryness under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.0 g, 6.75 mmol), 2,6-dichloro-4-fluorophenylamine (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0° C., warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis. a cooled warmed to room temperature stirred for an additional 2 h concentrated under reduced pressure The residue was dissolved in toluene filtered though a pad of Celite® The filtrate was concentrated to dryness under reduced pressure