2-bromo-4-chloro-6-fluorobenzonitrile

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and azidotrimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) was heated to 120° C. for 72 h. After completion of the reaction, the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml). The organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure to afford the title compound (4.2 g, 87%) as red solid. After completion of the reaction the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml) The organic layer was separated washed with water and brine dried with Na2SO4 concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-4-chloro-6-fluoro-phenylamine (10 g, 44.5 mmol) in anhydrous CH2Cl2 (100 ml) was added nitrosonium tetrafluoroborate (5.72 g, 49.01 mmol) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then cooled to 0° C. prior to addition of KCN (5.8 g, 89.1 mmol) followed by a dropwise addition of an aqueous solution (50 ml) of cupric sulfate hexahydrate (22.24 g, 89.1 mmol). After stirring for 40 minutes at 0° C., the reaction mixture was allowed to warm to 25° C. and stirring was continued for 1 h. The reaction mixture was diluted with CH2Cl2 (100 ml) and slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution was no longer observed. The resulting heterogeneous mixture was then filtered through a pad of celite and the organic layer was separated, washed twice with brine, dried with Na2SO4 and evaporated. The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10) to obtain the title compound (4 g, 38%) as reddish solid. The reaction mixture was then cooled to 0° C. After stirring for 40 minutes at 0° C. to warm to 25° C. stirring was continued for 1 h slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution The resulting heterogeneous mixture was then filtered through a pad of celite the organic layer was separated washed twice with brine dried with Na2SO4 evaporated The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10)

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

Procedure: A solution of 2-bromo-4-chloro-6-fluoroaniline (25.0 g, 111 mmol) in 200 mL of anhydrous DCM, in a 2 liter round-bottom flask equipped with a bubbler, was treated with nitrosonium tetrafluoroborate (14.3 g, 123 mmol), at ambient temperature. After 1 hour complete consumption of the aniline was observed. The reaction mixture was cooled to 0° C. prior to the addition of potassium cyanide (14.5 g, 223 mmol). With rapid stirring, an aqueous solution of cupric sulfate hexahydrate (55.6 g, 223 mmol in 125 mL of water) was slowly added producing a large volume of gas evolution. After stirring for 40 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 hour at ambient temperature, the reaction mixture was diluted with additional DCM and then slowly quenched by the addition of aqueous saturated sodium bicarbonate until additional gas evolution is no longer observed. The resulting heterogeneous mixture was then filtered through a large pad of celite, washing with DCM as needed. The organic filtrate was then washed twice with saturated brine prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to silica gel chromatography eluting with 0-25% DCM in heptane. Collection of product containing fractions and removal of solvent yielded 9.76 grams of 2-bromo-4-chloro-6-fluorobenzo-nitrile, which gave LC/MS and proton NMR spectra consistent with theory. After 1 hour complete consumption of the aniline producing a large volume of gas evolution the ice bath was removed to warm to ambient temperature After 1 hour at ambient temperature the reaction mixture was diluted with additional DCM slowly quenched by the addition of aqueous saturated sodium bicarbonate until additional gas evolution The resulting heterogeneous mixture was then filtered through a large pad of celite washing with DCM The organic filtrate was then washed twice with saturated brine to drying over sodium sulfate Filtration and solvent removal provided material which eluting with 0-25% DCM in heptane Collection of product containing fractions and removal of solvent

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

Procedure: The title compound was synthesized as described for Example 64i in 55% yield starting from 2-bromo-4-chloro-6-fluorobenzonitrile (6.35 g, 27.08 mmol) and 3-bromobenzoyl chloride (3.58 mL, 27.08 mmol).

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

Procedure: 2-Bromo-4-chloro-6-fluorobenzonitrile (6.95 g, 29.64 mmol) was dissolved in THF (15 mL) and added to a bottle of Rieke® Zinc in THF (50 mg/mL, 50.0 mL, 38.24 mmol) at 0° C. under an argon atmosphere. The resulting mixture was stirred at rt for 6 h and then stored in a refrigerator for 60 h allowing the excess of zinc to settle. The solution was carefully decanted off and cooled to −78° C. under an argon atmosphere. A solution of lithium bromide (5.15 g, 59.28 mmol) and copper(I) cyanide (2.65 g, 29.64 mmol) in THF (30 mL) was added and the resulting mixture was stirred at rt for 30 min. The mixture was cooled to −78° C. and then 3-methoxybenzoyl chloride (4.17 mL, 29.64 mmol) was added dropwise. The cooling bath was removed and the resulting mixture was stirred at rt for 1.5 h. Saturated aqueous NH4Cl (12 mL) was added to the mixture, the THF was removed in vacuo and the residue was diluted with water (50 mL) and DCM (50 mL). The mixture was poured into a phase separator, the organic phase was collected, concentrated and purified on a silica gel column (0-30% EtOAc in heptane) to give 4.7 g (55%) of the title compound. stored in a refrigerator for 60 h The solution was carefully decanted off cooled to −78° C. under an argon atmosphere the resulting mixture was stirred at rt for 30 min The mixture was cooled to −78° C. The cooling bath was removed the resulting mixture was stirred at rt for 1.5 h Saturated aqueous NH4Cl (12 mL) was added to the mixture the THF was removed in vacuo the residue was diluted with water (50 mL) and DCM (50 mL) The mixture was poured into a phase separator the organic phase was collected concentrated purified on a silica gel column (0-30% EtOAc in heptane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and azidotrimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) was heated to 120° C. for 72 h. After completion of the reaction, the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml). The organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated under reduced pressure to afford the title compound as red solid (4.2 g, 87%). After completion of the reaction the mixture was partitioned between EtOAc (50 ml) and aqueous 0.5N HCl solution (40 ml) The organic layer was separated washed with water and brine dried with Na2SO4 concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-4-chloro-6-fluoro-phenylamine (10 g, 44.5 mmol) in anhydrous DCM (100 ml) was added nitrosonium tetrafluoroborate (5.72 g, 49.01 mmol) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then cooled to 0° C. prior to addition of KCN (5.8 g, 89.1 mmol) followed by a dropwise addition of an aqueous solution (50 ml) of cupric sulfate hexahydrate (22.24 g, 89.1 mmol). After stirring for 40 minutes at 0° C. the reaction mixture was allowed to warm to 25° C. and stirring was continued for 1 h. The reaction mixture was diluted with DCM (100 ml) and slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution is no longer observed. The resulting heterogeneous mixture was then filtered through a pad of celite and the organic layer was separated, washed twice with brine, dried with Na2SO4 and evaporated. The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10) to obtain the title compound as reddish solid (4 g, 38%). The reaction mixture was then cooled to 0° C. After stirring for 40 minutes at 0° C. the reaction mixture to warm to 25° C. stirring was continued for 1 h slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution The resulting heterogeneous mixture was then filtered through a pad of celite the organic layer was separated washed twice with brine dried with Na2SO4 evaporated The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10)

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

Procedure: A solution of 2-bromo-4-chloro-6-fluoroaniline (25.0 g, 111 mmol) in 200 mL of anhydrous DCM, in a 2 liter round-bottom flask equipped with a bubbler, was treated with nitrosonium tetrafluoroborate (14.3 g, 123 mmol), at ambient temperature. After 1 hour complete consumption of the aniline was observed. The reaction mixture was cooled to 0° C. prior to the addition of potassium cyanide (14.5 g, 223 mmol). With rapid stirring, an aqueous solution of cupric sulfate hexahydrate (55.6 g, 223 mmol in 125 mL of water) was slowly added producing a large volume of gas evolution. After stirring for 40 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 hour at ambient temperature, the reaction mixture was diluted with additional DCM and then slowly quenched by the addition of aqueous saturated sodium bicarbonate until additional gas evolution is no longer observed. The resulting heterogeneous mixture was then filtered through a large pad of celite, washing with DCM as needed. The organic filtrate was then washed twice with saturated brine prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to silica gel chromatography eluting with 0-25% DCM in heptane. Collection of product containing fractions and removal of solvent yielded 9.76 grams of 2-bromo-4-chloro-6-fluorobenzo-nitrile, which gave LC/MS and proton NMR spectra consistent with theory. After 1 hour complete consumption of the aniline producing a large volume of gas evolution the ice bath was removed to warm to ambient temperature After 1 hour at ambient temperature the reaction mixture was diluted with additional DCM slowly quenched by the addition of aqueous saturated sodium bicarbonate until additional gas evolution The resulting heterogeneous mixture was then filtered through a large pad of celite washing with DCM The organic filtrate was then washed twice with saturated brine to drying over sodium sulfate Filtration and solvent removal provided material which eluting with 0-25% DCM in heptane Collection of product containing fractions and removal of solvent