4-BROMO-1-ETHOXY-2-FLUOROBENZENE

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

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred virgorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were dired over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodium sulphate concentrated by evaporation under reduced pressure

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

Procedure: Under a nitrogen atmosphere, a mixture of 4-bromo-2-fluoro-1-phenol (52) (10.8 g, 56.58 mmol), 1-(bromomethyl)-4-propylcyclohexane (60) (12.4 g, 56.58 mmol) and potassium carbonate (15.6 g, 112.9 mmol) was agitated at 80° C. for 5 hours in 100 mL of DMF. The reaction mixture was quenched with 100 mL of water, and extracted with 60 mL of toluene three times. Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (61) (11.4 g, yield 61.2%) was obtained. The reaction mixture was quenched with 100 mL of water extracted with 60 mL of toluene three times Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine dried over magnesium sulfate a solvent was distilled off by an evaporator The residue was purified by silica gel column chromatography

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred vigorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were then dried over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodim sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane the combined organic layers were then dried over anhydrous sodium sulphate The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodim sulphate concentrated by evaporation under reduced pressure

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred vigorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were then dried over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodim sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane the combined organic layers were then dried over anhydrous sodium sulphate The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodim sulphate concentrated by evaporation under reduced pressure

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred virgorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were dired over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodium sulphate concentrated by evaporation under reduced pressure

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred virgorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were dired over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodium sulphate concentrated by evaporation under reduced pressure

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

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 ml of a THF solution of 22.8 g (104 mmol) of 3-fluoro-4-ethoxybromobenzene was dropped, while stirring, at 40 to 60° C. to 3.03 g (124.8 mmol) of dried turnings magnesium, and refluxed under heating after dropping for one hour. The solution was cooled by a coolant to −70° C. and, a THF solution of 16 ml (132.5 mmol) of trimethyl borate (THF: 70 ml) was dropped under stirring. After stirring at −70° C. for 3 hours, and further stirring at a room temperature for 20 hours, the reaction solution was cooled to 5° C., and 50 ml of 6M hydrochloric acid was added. After separating the organic layer, the aqueous layer was extracted with 100 ml of ethyl acetate. After mixing the organic layer, it was washed with water and then with an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure, to obtain 22.3 g of crude 3-fluoro-4-ethoxyphenyl boronic acid. The obtained crude boronic acid derivative was used without purification for a second step. refluxed under heating After stirring at −70° C. for 3 hours further stirring at a room temperature for 20 hours the reaction solution was cooled to 5° C. After separating the organic layer the aqueous layer was extracted with 100 ml of ethyl acetate After mixing the organic layer, it was washed with water with an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate concentrated under a reduced pressure

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

Procedure: Under a nitrogen atmosphere, a mixture of 4-bromo-2-fluoro-1-phenol (52) (10.8 g, 56.58 mmol), 1-(bromomethyl)-4-propylcyclohexane (60) (12.4 g, 56.58 mmol) and potassium carbonate (15.6 g, 112.9 mmol) was agitated at 80° C. for 5 hours in 100 mL of DMF. The reaction mixture was quenched with 100 mL of water, and extracted with 60 mL of toluene three times. Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(4-propylcyclohexyl)benzene (61) (11.4 g, yield 61.2%) was obtained. The reaction mixture was quenched with 100 mL of water extracted with 60 mL of toluene three times Combined organic layers were washed with a 2N sodium hydroxide aqueous solution, water and saturated brine dried over magnesium sulfate a solvent was distilled off by an evaporator The residue was purified by silica gel column chromatography

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

Procedure: A mixture of 2-fluoro-4-bromophenol (19.1 g), sodium hydroxide (6 g), ethyl iodide (46.8 g), tetra-n-butylammonium bromide (3.2 g), dichloromethane (250 cm3) and water (250 cm3) was stirred vigorously at the ambient temperature for 51/2 hours, then allowed to stand for a further 68 hours. The organic layer was separated and the aqueous layer was washed with dichloromethane; the combined organic layers were then dried over anhydrous sodium sulphate. The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C. The residual oil was purified by column chromatography on a silica gel support, eluting firstly with n-hexane and secondly with dichloromethane. The product-containing fractions were combined, washed with an aqueous solution of sodium metabisulphite, dried over anhydrous sodim sulphate and concentrated by evaporation under reduced pressure to give 4-bromo-2-fluorophenetole (15.2 g) as an oil. The product was shown by gas liquid chromatography to be 93% pure, and was used without further purification. to stand for a further 68 hours The organic layer was separated the aqueous layer was washed with dichloromethane the combined organic layers were then dried over anhydrous sodium sulphate The solvent was removed by evaporation under reduced pressure at a bath temperature maintained below 40° C The residual oil was purified by column chromatography on a silica gel support eluting firstly with n-hexane and secondly with dichloromethane washed with an aqueous solution of sodium metabisulphite dried over anhydrous sodim sulphate concentrated by evaporation under reduced pressure

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

Procedure: 2.00 g (5.24 mmol) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromen-6-one, the compound of Example 841, were dissolved in 12 ml of THF, and 2.37 ml (23.0 mmol) of boron trifluoride/THF complex were added with ice-cooling. 24 ml of ethylene glycol dimethyl ether and then in portions 530 mg of sodium borohydride were subsequently added. The mixture was subsequently stirred at room temperature for 18 hours and then transferred onto ice. The mixture was subjected to conventional purification, giving 1.5 g (78% of theory) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromene as colourless crystals. These were dissolved in THF, hydrogenated at a pressure of 1 bar in the presence of 0.6 g of Pd/C (5%), filtered and evaporated, giving 1.2 g (99% of theory) of 8-ethoxy-4,7-difluoro-3-hydroxy-6H-benzo[c]chromene as colourless crystals. 2.37 ml (23.0 mmol) of boron trifluoride/THF complex were added with ice- cooling The mixture was subjected to conventional purification