methyl 3-(bromomethyl)-4-chlorobenzoate

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

実験手順: 1.0 M LiHMDS (5.00 ml, 5.00 mmol) in THF/ethylbenzene was added slowly to a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.12 g, 5 mmol) in THF (50 ml) under nitrogen at ambient temperature. The solution was stirred for 20 min and a solution of methyl 3-(bromomethyl)-4-chlorobenzoate (1.32 g, 5.0 mmol, synthesised according to WO2006079857) in THF (4 ml) was added in one portion. The solution was stirred for 2 h and left overnight. The solution was treated with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried (Na2SO4), filtered and solvent evaporated in vacuo. The residue was purified on a silica cartridge (50 g) eluted with 0-100% cyclohexane/EtOAc to give the title compound (1.95 g) as a white solid after evaporation from diethyl ether; LCMS: (System 4) MH+=406/408, tRET=2.69 min. at ambient temperature The solution was stirred for 2 h left overnight extracted with ethyl acetate (2×50 ml) The combined organic extracts were dried (Na2SO4) filtered solvent evaporated in vacuo The residue was purified on a silica cartridge (50 g) eluted with 0-100% cyclohexane/EtOAc

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: The mixture was then cooled the white precipitate was removed by filtration The filtrate was concentrated the resulting solid was re-crystallized from ethyl acetate

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H). The mixture was then cooled the white precipitate was removed by filtration The filtrate was concentrated the resulting solid was re-crystallized from ethyl acetate

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 16.0 g of the obtained methyl 3-bromomethyl-4-chlorobenzoate, 15.0 g of potassium cyanate and 35 ml of methanol were added to 200 ml of N,N-dimethylformamide, followed by stirring at 90° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropanol to obtain 25.2 g of methyl 4-chloro-3-(methoxycarbonylaminomethyl)benzoate as white crystals. the organic layer was dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained crude crystals were washed with isopropanol

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 16.0 g of the obtained methyl 3-bromomethyl-4-chlorobenzoate, 15.0 g of potassium cyanate and 35 ml of methanol were added to 200 ml of N,N-dimethylformamide, followed by stirring at 90° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropanol to obtain 25.2 g of methyl 4-chloro-3-(methoxycarbonylaminomethyl)benzoate as white crystals. the organic layer was dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained crude crystals were washed with isopropanol

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

実験手順: 40.4 g of methyl 4-chloro-3-methylbenzoate, 39 g of N-bromosuccinimide and 1 g of azobisisobutyronitrile were added to 300 ml of carbon tetrachloride, followed by reflux under heating for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insoluble matters were collected by filtration and the filtrate was concentrated. The obtained crude crystals were washed with hexane to obtain 34.3 g of methyl 3-bromomethyl-4-chlorobenzoate as white crystals. by reflux under heating for 4 hours After completion of the reaction insoluble matters were collected by filtration the filtrate was concentrated The obtained crude crystals were washed with hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H). The mixture was then cooled the white precipitate was removed by filtration The filtrate was concentrated the resulting solid was re-crystallized from ethyl acetate

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H) 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H) The mixture was then cooled the white precipitate was removed by filtration The filtrate was concentrated the resulting solid was re-crystallized from ethyl acetate