4-bromo-3-chloro-5-fluoroaniline

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-3-chloro-5-fluoroaniline (2.08 g, 9.27 mmol) and copper(I)cyanide (0.83 g, 9.27 mmol) in DMF (15 ml) was heated in microwave reactor at 190° C. for 1 h. Reaction mixture was poured into 12% ammonium hydroxide (200 ml) and stirred for 30 min. Thus formed precipitate was filtered, washed with water and dried in vacuum to obtain 1.21 g (77%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (dd, 1H), 6.60 (m, 1H), 6.86 (bs, 2H). Reaction mixture Thus formed precipitate was filtered washed with water dried in vacuum

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

Procedure: To a cooled (0° C.) solution of 3-chloro-5-fluoroaniline (5.0 g, 33 mmol) in MeCN (50 ml) was added a suspension of N-bromosuccinimide (5.9 g, 33 mmol) in MeCN (10 ml). After being stirred for 2 h at RT the reaction was quenched by adding 10% NaHSO3 (50 ml). The mixture was concentrated to about half of the volume, diluted with water (50 ml) and extracted with EtOAc (3×50 ml). Combined organic phases were dried over Na2SO4 and evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 5.5 g (74%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 5.88 (bs, 2H), 6.45 (dd, 1H), 6.64 (m, 1H). was added was quenched by adding 10% NaHSO3 (50 ml) The mixture was concentrated to about half of the volume diluted with water (50 ml) extracted with EtOAc (3×50 ml) Combined organic phases were dried over Na2SO4 evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane)

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

Procedure: To a cooled (0° C.) solution of 3-chloro-5-fluoroaniline (5.0 g, 33 mmol) in MeCN (50 ml) was added a suspension of N-bromosuccinimide (5.9 g, 33 mmol) in MeCN (10 ml). After being stirred for 2 h at RT the reaction was quenched by adding 10% NaHSO3 (50 ml). The mixture was concentrated to about half of the volume, diluted with water (50 ml) and extracted with EtOAc (3×50 ml). Combined organic phases were dried over Na2SO4 and evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 5.5 g (74%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 5.88 (bs, 2H), 6.45 (dd, 1H), 6.64 (m, 1H). was added was quenched by adding 10% NaHSO3 (50 ml) The mixture was concentrated to about half of the volume diluted with water (50 ml) extracted with EtOAc (3×50 ml) Combined organic phases were dried over Na2SO4 evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g), copper(I)cyanide (980 mmol, 88 g) and NMP (1000 ml) were added into the reaction flask, heated up to 160° C. and stirred for 3 h to complete the reaction. The reaction mixture was cooled to RT. Water and 25% ammonia solution was added keeping the mixture at RT. The mixture was stirred overnight and the formed precipitate was separated by filtration and flushed with water. The filtered precipitate was dried under vacuum to give 117.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.41-6.47 (m, 1H), 6.58-6.62 (m, 1H), 6.86 (bs, 2H). the reaction The reaction mixture was cooled to RT at RT The mixture was stirred overnight the formed precipitate was separated by filtration flushed with water The filtered precipitate was dried under vacuum

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

Procedure: 3-Chloro-5-fluoroaniline (2061 mmol, 300 g) was dissolved in ACN (3000 ml) and the solution cooled to 0° C. NBS (2061 mmol, 367 g) was added to the reaction mixture in small portions keeping the temperature below 10° C. Reaction mixture was stirred at 10±5° C. for 3.5 h. 10% Aqueous NaHSO3 was added and the reaction mixture was concentrated under vacuum to remove organic solvents. Water and DCM was added, stirred for 15 min and the phases were separated. The water phase was extracted with DCM. The combined organics were washed with water. The organic phase was evaporated. 2-Propanol was added to the residue and distilled until the steam temperature was 80° C. Water was added and the temperature was kept at 40±10° C. The mixture was cooled to 5° C. and stirred for 4 h. The precipitate was removed by filtration, washed with water and dried under vacuum. 440.7 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 5.87 (s, 2H), 6.42-6.49 (m, 1H), 6.62-6.66 (m, 1H). the temperature below 10° C Reaction mixture the reaction mixture was concentrated under vacuum to remove organic solvents Water and DCM was added stirred for 15 min the phases were separated The water phase was extracted with DCM The combined organics were washed with water The organic phase was evaporated 2-Propanol was added to the residue distilled until the steam temperature was 80° C Water was added was kept at 40±10° C The mixture was cooled to 5° C. stirred for 4 h The precipitate was removed by filtration washed with water dried under vacuum

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-3-chloro-5-fluoroaniline (2.08 g, 9.27 mmol) and copper(I)cyanide (0.83 g, 9.27 mmol) in DMF (15 ml) was heated in microwave reactor at 190° C. for 1 h. Reaction mixture was poured into 12% ammonium hydroxide (200 ml) and stirred for 30 min. Thus formed precipitate was filtered, washed with water and dried in vacuum to obtain 1.21 g (77%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (dd, 1H), 6.60 (m, 1H), 6.86 (bs, 2H). Reaction mixture Thus formed precipitate was filtered washed with water dried in vacuum

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

Procedure: To a cooled (0° C.) solution of 3-chloro-5-fluoroaniline (5.0 g, 33 mmol) in MeCN (50 ml) was added a suspension of N-bromosuccinimide (5.9 g, 33 mmol) in MeCN (10 ml). After being stirred for 2 h at RT the reaction was quenched by adding 10% NaHSO3 (50 ml). The mixture was concentrated to about half of the volume, diluted with water (50 ml) and extracted with EtOAc (3×50 ml). Combined organic phases were dried over Na2SO4 and evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 5.5 g (74%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 5.88 (bs, 2H), 6.45 (dd, 1H), 6.64 (m, 1H). was added was quenched by adding 10% NaHSO3 (50 ml) The mixture was concentrated to about half of the volume diluted with water (50 ml) extracted with EtOAc (3×50 ml) Combined organic phases were dried over Na2SO4 evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane)