5-bromo-1,3-difluoro-2-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1]

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-bromo-1,3-difluoro-2-methyl-benzene (6.910 g; 33.379 mmol) in anhydrous DMF (200 ml) were added successively butyl acrylate (7.15 ml; 50.062 mmol), DABCO (157 mg; 1.333 mmol), potassium carbonate (4.612 g; 33.379 mmol), and palladium acetate (150 mg; 0.669 mmol). The resulting brown suspension was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to rt before ether (400 ml) was added. This mixture was then washed with water (2×200 ml), and the mixed aq. layers were further extracted with ether (150 ml). The combined organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/heptane=1/1=>DCM) gave the pure product 3-(3,5-difluoro-4-methyl-phenyl)-acrylic acid butyl ester as a yellow oil which was further dried under HV (4.690 g; 55%). LC-MS: tR=1.10 min.; [M+H]+: no ionisation. was added This mixture was then washed with water (2×200 ml) the mixed aq. layers were further extracted with ether (150 ml) The combined organic layers were dried over anh. MgSO4 filtered concentrated to dryness under reduced pressure Purification by FC (DCM/heptane=1/1=>DCM)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent: hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20°C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20°C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20° C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene. at -20° C is dropwise added over 30 minutes The temperature of the resulting reaction mixture is elevated to -40° C. is then added is elevated to room temperature after which the resulting organic layer is separated washed successively with water a saturated saline solution and then dried over anhydrous magnesium sulfate Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1]