1,3-dibromo-5-fluoro-2-methoxybenzene

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: 1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 h. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) is chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76%. dry degassed 1,4-dioxane heated to reflux for 3 h After cooling down the mixture was filtrated evaporated The remaining solid (22 g) is chromatographed on silica gel

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil. was added, dropwise over 0.5 h extracted with dichloromethane (3×150 mL) The combined extracts were dried (Na2SO4) evaporated in vacuo to give a brown oil Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid was hydrogenated at 20° C. Catalyst was removed by filtration the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL) The combined organic extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography on silica with 20-50% ether in hexane gradient elution

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil. was added, dropwise over 0.5 h extracted with dichloromethane (3×150 mL) The combined extracts were dried (Na2SO4) evaporated in vacuo to give a brown oil Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid was hydrogenated at 20° C. Catalyst was removed by filtration the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL) The combined organic extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography on silica with 20-50% ether in hexane gradient elution

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

実験手順: 1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 h. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) is chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76%. dry degassed 1,4-dioxane heated to reflux for 3 h After cooling down the mixture was filtrated evaporated The remaining solid (22 g) is chromatographed on silica gel

反応条件: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of c.H2SO4 (740 mL) at 0 to 5° C. was added 1,3-dibromo-5-fluoro-2-methoxybenzene (223.3 g, 0.786 mol). A solution of fuming nitric acid (90%, 38 mL, 0.815 mol) in c.H2SO4 (740 mL) was added dropwise, maintaining the temperature between 0 and 5° C. The reaction mixture was stirred at 3 to 5° C. for 2 hours, quenched into ice (2.2 kg) and extracted with dichloromethane (3×2 L). The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L), dried over Na2SO4, filtered and the filter cake washed with DCM (3×400 mL). The filtrate was concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxy-4-nitrobenzene as a pale orange crystalline solid (244.9 g, 95%). maintaining the temperature between 0 and 5° C quenched into ice (2.2 kg) extracted with dichloromethane (3×2 L) The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L) dried over Na2SO4 filtered the filter cake washed with DCM (3×400 mL) The filtrate was concentrated in vacuo at 40° C.

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 2,6-dibromo-4-fluorophenol (214.5 g, 0.794 mol) in acetone (4.3 L), potassium carbonate (120.6 g, 0.874 mol) and methyl iodide (54.4 mL, 0.874 mol) were added at room temperature. The mixture was heated to reflux for 1.5 hours cooled to 25° C. and filtered, washing the filter cake with dichloromethane (2×1.5 L). The filtrate was concentrated in vacuo at 40° C. The crude product was slurred in dichloromethane (1 L) for 30 minutes at 25° C., filtered and concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxybenzene as an off-white crystalline solid (223.3 g, 98.9%). The mixture was heated to reflux for 1.5 hours filtered washing the filter cake with dichloromethane (2×1.5 L) The filtrate was concentrated in vacuo at 40° C filtered concentrated in vacuo at 40° C.

反応条件: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of c.H2SO4 (740 mL) at 0 to 5° C. was added 1,3-dibromo-5-fluoro-2-methoxybenzene (223.3 g, 0.786 mol). A solution of fuming nitric acid (90%, 38 mL, 0.815 mol) in c.H2SO4 (740 mL) was added dropwise, maintaining the temperature between 0 and 5° C. The reaction mixture was stirred at 3 to 5° C. for 2 hours, quenched into ice (2.2 kg) and extracted with dichloromethane (3×2 L). The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L), dried over Na2SO4, filtered and the filter cake washed with DCM (3×400 mL). The filtrate was concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxy-4-nitrobenzene as a pale orange crystalline solid (244.9 g, 95%). maintaining the temperature between 0 and 5° C quenched into ice (2.2 kg) extracted with dichloromethane (3×2 L) The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L) dried over Na2SO4 filtered the filter cake washed with DCM (3×400 mL) The filtrate was concentrated in vacuo at 40° C.

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 2,6-dibromo-4-fluorophenol (214.5 g, 0.794 mol) in acetone (4.3 L), potassium carbonate (120.6 g, 0.874 mol) and methyl iodide (54.4 mL, 0.874 mol) were added at room temperature. The mixture was heated to reflux for 1.5 hours cooled to 25° C. and filtered, washing the filter cake with dichloromethane (2×1.5 L). The filtrate was concentrated in vacuo at 40° C. The crude product was slurred in dichloromethane (1 L) for 30 minutes at 25° C., filtered and concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxybenzene as an off-white crystalline solid (223.3 g, 98.9%). The mixture was heated to reflux for 1.5 hours filtered washing the filter cake with dichloromethane (2×1.5 L) The filtrate was concentrated in vacuo at 40° C filtered concentrated in vacuo at 40° C.

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

実験手順: 1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2 dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 hours. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) was chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76% dry degassed 1,4-dioxane heated to reflux for 3 hours After cooling down the mixture was filtrated evaporated The remaining solid (22 g) was chromatographed on silica gel

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

実験手順: The solution of 8-3 (273.4 g, 0.963 mol) dissolved in concentrated H2SO4 (1.6 L) at 0° C. The mixture of conc.HNO3 (63.2 mL) and conc. H2SO4 (400 mL) was added dropwise over 1 h. The color of the reaction became orange. TLC monitored the starting material was disappeared. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate (800 mL×3). The combined organic layers were combined and were concentrated in vacuo to 400 mL, which was cooled under ice bath to afforded 8-4 (234.2 g, 73.9%) as a white solid. The mixture of conc The reaction mixture was poured onto crushed ice extracted with ethyl acetate (800 mL×3) were concentrated in vacuo to 400 mL, which was cooled under ice bath

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil. was added, dropwise over 0.5 h extracted with dichloromethane (3×150 mL) The combined extracts were dried (Na2SO4) evaporated in vacuo to give a brown oil Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid was hydrogenated at 20° C. Catalyst was removed by filtration the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL) The combined organic extracts were dried (Na2SO4) evaporated in vacuo to give an oil Chromatography on silica with 20-50% ether in hexane gradient elution