2-bromo-3-fluoroaniline

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

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Flask A: A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, condenser, and temperature probe; the flask was charged with hydroxylamine hydrochloride (Fluka; 12.47 g, 179 mmol), Na2SO4 (51.7 g, 364 mmol), 2,2,2-trichloro-1-ethoxyethanol (15.78 g, 82 mmol), and water (240 ml). This was stirred to 40° C. to affect dissolution. Flask B: A mixture of 2-bromo-3-fluoroaniline (10.33 g, 54.4 mmol) in water (32.0 mL)/conc. HCl (14.95 mL, 179 mmol) was stirred at RT and then at 50° C. to attempt dissolution; EtOH (10 mL) was added as another attempt to dissolve the aniline to no avail. The fine slurry was added to Flask A containing the stirring 2,2,2-trichloro-1-ethoxyethanol solution at 40° C. The reaction was heated to 100° C. and was stirred for 1 h. The reaction was cooled to 5° C. in an ice bath, filtered through a disposable 0.45 micron ZapCap filter (very slow filtration), and washed with water to give N-(2-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (12.34 g, 47.3 mmol, 87% yield) as a brown solid after it was dried in a vacuum oven. 1H NMR (400 MHz, CDCl3) δ ppm 6.92 (td, J=8.31, 1.37 Hz, 1H), 7.32 (td, J=8.31, 6.26 Hz, 1H), 7.60 (s, 1H), 7.87 (s, 1H), 8.25 (d, J=8.41 Hz, 1H), 8.98 (br. s., 1H). 19F NMR (377 MHz, CDCl3) δ ppm −104.01 (s, 1F). MS (ESI, pos. ion) m/z: 260.9/262.9 (M+1). Flask A: A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, condenser dissolution at 50° C. dissolution The reaction was heated to 100° C. was stirred for 1 h The reaction was cooled to 5° C. in an ice bath filtered through a disposable 0.45 micron ZapCap filter ( very slow filtration), and washed with water

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

Procedure: To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2Cl2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0° C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step. the mixture was extracted with CH2Cl2 (50 mL×3) evaporated under vacuum

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

Procedure: To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 mL) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H). After the addition the mixture was extracted with EtOAc (20 mL×3) The organic layers were dried over anhydrous Na2SO4 evaporated under vacuum

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

Procedure: To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2Cl2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0° C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step. the mixture was extracted with CH2Cl2 (50 mL×3) evaporated under vacuum

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

Procedure: To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2Cl2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0° C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step. the mixture was extracted with CH2Cl2 (50 mL×3) evaporated under vacuum

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

Procedure: To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 L) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H). After the addition the mixture was extracted with EtOAc (20 mL×3) The organic layers were dried over anhydrous Na2SO4 evaporated under vacuum

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

Procedure: To a solution of 2-bromo-1-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in CH3OH (50 L) was added NiCl2 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0° C. After the addition, the mixture was stirred for 5 min. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.07-7.02 (m, 1H), 6.55-6.49 (m, 1H), 4.22 (br s, 2H). After the addition the mixture was extracted with EtOAc (20 mL×3) The organic layers were dried over anhydrous Na2SO4 evaporated under vacuum

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.0.22 mmol) in toluene (5 mL), triphosgene (26 mg, 0.09 mmol) and triethyl amine (0.04 mL, 0.26 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours. Then the reaction mixture was concentrated under reduced pressure and then it was added to 3-amino-6-chloro-2-hydroxybenzenesulfonamide (44 mg, 0.22 mmol) in DMF (1 mL), The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (30%Ethyl acetate/Hexane) gave desired product (7 mg, 7%). EI-MS m/z 439.6 (M+). Then the reaction mixture was concentrated under reduced pressure The reaction mixture was stirred at room temperature for 16 hours

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.0.22 mmol) in toluene (5 mL), triphosgene (26 mg, 0.09 mmol) and triethyl amine (0.04 mL, 0.26 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours. Then the reaction mixture was concentrated under reduced pressure and then it was added to 3-amino-6-chloro-2-hydroxybenzenesulfonamide (44 mg, 0.22 mmol) in DMF (1 mL), The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (30%Ethyl acetate/Hexane) gave desired product (7 mg, 7%). EI-MS m/z 439.6 (M+). Then the reaction mixture was concentrated under reduced pressure The reaction mixture was stirred at room temperature for 16 hours

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-3-fluoroaniline (42 mg, 0.0.22 mmol) in toluene (5 mL), triphosgene (26 mg, 0.09 mmol) and triethyl amine (0.04 mL, 0.26 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours. Then the reaction mixture was concentrated under reduced pressure and then it was added to 3-amino-6-chloro-2-hydroxybenzenesulfonamide (44 mg, 0.22 mmol) in DMF (1 mL), The reaction mixture was stirred at room temperature for 16 hours. Chromatography of the resulting liquid on silica gel (30%Ethyl acetate/Hexane) gave desired product (7 mg, 7%). EI-MS m/z 439.6 (M+). Then the reaction mixture was concentrated under reduced pressure The reaction mixture was stirred at room temperature for 16 hours