4-溴-2,3-二氟苯胺

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask, 4-bromo-2,3-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.051 g, 4.97 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature and blowing nitrogen gently over the solution, the desired product began to precipitate and was collected by filtration and dried via vacuum filtration to afford the title product (1400 mg, 63%). MS(ES)+ m/e 445.1, 447.1 M+H]+. to warm to room temperature The solution was re-cooled to −78° C. to warm to room temperature

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask, 4-bromo-2,3-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.051 g, 4.97 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature and blowing nitrogen gently over the solution, the desired product began to precipitate and was collected by filtration and dried via vacuum filtration to afford the title product (1400 mg, 63%). MS(ES)+ m/e 445.1, 447.1 M+H]+. to warm to room temperature The solution was re-cooled to −78° C. to warm to room temperature

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min). The cooled reaction mixture washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate evaporated under reduced pressure to get the crude product The crude was purified by column chromatography

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min). The cooled reaction mixture washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate evaporated under reduced pressure to get the crude product The crude was purified by column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The procedure for preparing this compound was based on that described in International Patent Publication No. WO 2010/091272. To a 100 mL round bottom flask, 2,3-difluoroaniline (1 g, 0.0077 mol) and ACN (30 mL) were added. To the flask was added the solution of tetrabutylammonium tribromide (3.71 g, 0.0077 mol, in 10 mL of ACN). The reaction mixture was stirred at room temperature for 3 h. The reaction mass was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-12 silica gel and 30% ethyl acetate in hexane to get the title compound [0.55 g, 34%]. The obtained product was immediately taken to the next step. The procedure for preparing this compound extracted with ethyl acetate The ethyl acetate layer was washed with brine evaporated under reduced pressure to get the crude product The crude product was purified by column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 2,3-difluoroaniline (20 g, 154.9 mmol) in HOAc (230 mL) was added over 1 hour a solution of bromine (24.75 g, 7.978 mL, 154.9 mmol) in HOAc (70 mL) at RT. The reaction mixture was stirred at RT for another 1 hour and a white precipitate appeared. The solvent was removed under reduced pressure, the residue was made basic with 6M NaOH at 0° C., and the basic solution was extracted with DCM. After drying the organics over MgSO4, the volatiles were removed in vacuo to provide 4-bromo-2,3-difluoroaniline (Compound 1079); LC/MS (M+H)=207.96. This compound was reacted with the acyl chloride of 2-fluoronicotinic acid and carried through the sequence of reactions as described in Example 19 to produce N-tert-butyl-3-(1-(4-bromo-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1080); 1H NMR (300 MHz, DMSO-d6): δ 8.21 (dd, J=1.9, 4.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.54-7.48 (m, 1H), 7.44 (dd, J=1.9, 7.7 Hz, 1H), 6.71 (s, 1H), 6.58 (dd, J=4.8, 7.7 Hz, 1H) and 1.31 (s, 9H). The solvent was removed under reduced pressure was made basic with 6M NaOH at 0° C. the basic solution was extracted with DCM After drying the organics over MgSO4 the volatiles were removed in vacuo

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask, 4-bromo-2,3-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.051 g, 4.97 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature and blowing nitrogen gently over the solution, the desired product began to precipitate and was collected by filtration and dried via vacuum filtration to afford the title product (1400 mg, 63%). MS(ES)+ m/e 445.1, 447.1 M+H]+. to warm to room temperature The solution was re-cooled to −78° C. to warm to room temperature

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a round bottom flask, 4-bromo-2,3-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.051 g, 4.97 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature and blowing nitrogen gently over the solution, the desired product began to precipitate and was collected by filtration and dried via vacuum filtration to afford the title product (1400 mg, 63%). MS(ES)+ m/e 445.1, 447.1 M+H]+. to warm to room temperature The solution was re-cooled to −78° C. to warm to room temperature

反应条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min). The cooled reaction mixture washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate evaporated under reduced pressure to get the crude product The crude was purified by column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The procedure for preparing this compound was based on that described in International Patent Publication No. WO 2010/091272. To a 100 mL round bottom flask, 2,3-difluoroaniline (1 g, 0.0077 mol) and ACN (30 mL) were added. To the flask was added the solution of tetrabutylammonium tribromide (3.71 g, 0.0077 mol, in 10 mL of ACN). The reaction mixture was stirred at room temperature for 3 h. The reaction mass was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-12 silica gel and 30% ethyl acetate in hexane to get the title compound [0.55 g, 34%]. The obtained product was immediately taken to the next step. The procedure for preparing this compound extracted with ethyl acetate The ethyl acetate layer was washed with brine evaporated under reduced pressure to get the crude product The crude product was purified by column chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2,3-difluoro-phenylamine (13.45 g, 104.2 mmol) was diluted with acetic acid (180 ml), bromine (2.6 ml) diluted with acetic acid (5 ml) was slowly added thereto at 0° C., and the solution was stirred for 5 hours. The resulting solution was distilled under a reduced pressure to remove the solvent, basified by adding 50% sodium hydroxide solution (250 ml), and extracted with dichloromethane (200 ml) twice. The separated organic layer was dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain the title compound 6.46 g (yield: 30%). was slowly added The resulting solution was distilled under a reduced pressure to remove the solvent by adding 50% sodium hydroxide solution (250 ml) extracted with dichloromethane (200 ml) twice The separated organic layer was dried over magnesium sulfate filtered distilled under a reduced pressure