Methyl 2-chloro-4,5-difluorobenzoate

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: 2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolved in 20 mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was added followed by iodomethane (1.0 mL, 15 mmol). This reaction mixture was heated under reflux for 1 h and then cooled to room temperature. This suspension was then diluted with 40 mL of ethyl ether. The solid was removed by filtration and washed with ethyl ether. The filtrate was evaporated in vacuo to give the title compound in quantitative yield as a clear oil. This reaction mixture was heated under reflux for 1 h The solid was removed by filtration washed with ethyl ether The filtrate was evaporated in vacuo

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

実験手順: To 2-chloro-4,5-difluoro-benzoic acid methyl ester (119, 5.70 g, 0.0276 mol) in tetrahydrofuran (120.0 mL), 1.00 M of lithium tetrahydroaluminate in tetrahydrofuran (30.0 mL) was added slowly under an atmosphere of nitrogen. The reaction was stirred at room temperature for 4 hours, followed by adding sodium sulfate decahydrate. After 30 minutes, the reaction mixture was filtered, concentrated and purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%). After 30 minutes the reaction mixture was filtered concentrated purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%)

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

実験手順: To 2-chloro-4,5-difluoro-benzoic acid methyl ester (119, 5.70 g, 0.0276 mol) in tetrahydrofuran (120.0 mL), 1.00 M of lithium tetrahydroaluminate in tetrahydrofuran (30.0 mL) was added slowly under an atmosphere of nitrogen. The reaction was stirred at room temperature for 4 hours, followed by adding sodium sulfate decahydrate. After 30 minutes, the reaction mixture was filtered, concentrated and purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%). After 30 minutes the reaction mixture was filtered concentrated purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-chloro-4,5-difluoro-benzoic acid (118, 14.0 g, 0.0727 mol) in methanol (100 mL) was added sulfuric acid (concentrated, 98%, 2.00 mL, 0.0375 mol). The reaction was stirred at 60° C. for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-chloro-4,5-difluoro-benzoic acid (118, 14.0 g, 0.0727 mol) in methanol (100 mL) was added sulfuric acid (concentrated, 98%, 2.00 mL, 0.0375 mol). The reaction was stirred at 60° C. for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 23.1 g (112 mmol) 22a and 231 ml dimethylsulphoxid were added 10.0 g (123 mmol) dimethylamine hydrochloride and 32.4 g (234 mmol) potassium carbonate. The reaction mixture was stirred for 24 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 22b was obtained in 89.5% yield (23.1 g 100 mmol). was reduced with high vacuum rotation evaporator at 65° C The residue was diluted with dichloromethane washed twice with water The combined water phases were extracted with dichloromethane The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The oily crude was purified by column chromatography

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

実験手順: To a stirred suspension of 5.0 g (26 mmol) 2-Chloro-4,5-difluoro-benzoic acid (Apollo) and 50 ml methanol were added 7.41 ml (104 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 22a was obtained in 84% yield (4.51 g, 21.8 mmol). drop wisely at 0° C filtered concentrated The residue was diluted with dichloromethane washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The residue was purified by column chromatography (hexane:ethylacetate)

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

実験手順: 2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolved in 20 mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was added followed by iodomethane (1.0 mL, 15 mmol). This reaction mixture was heated under reflux for 1 h and then cooled to room temperature. This suspension was then diluted with 40 mL of ethyl ether. The solid was removed by filtration and washed with ethyl ether. The filtrate was evaporated in vacuo to give the title compound in quantitative yield as a clear oil. This reaction mixture was heated under reflux for 1 h The solid was removed by filtration washed with ethyl ether The filtrate was evaporated in vacuo

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

実験手順: 2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolved in 20 mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was added followed by iodomethane (1.0 mL, 15 mmol). This reaction mixture was heated under reflux for 1 h and then cooled to room temperature. This suspension was then diluted with 40 mL of ethyl ether. The solid was removed by filtration and washed with ethyl ether. The filtrate was evaporated in vacuo to give the title compound in quantitative yield as a clear oil. This reaction mixture was heated under reflux for 1 h The solid was removed by filtration washed with ethyl ether The filtrate was evaporated in vacuo

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

実験手順: To 2-chloro-4,5-difluoro-benzoic acid methyl ester (119, 5.70 g, 0.0276 mol) in tetrahydrofuran (120.0 mL), 1.00 M of lithium tetrahydroaluminate in tetrahydrofuran (30.0 mL) was added slowly under an atmosphere of nitrogen. The reaction was stirred at room temperature for 4 hours, followed by adding sodium sulfate decahydrate. After 30 minutes, the reaction mixture was filtered, concentrated and purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%). After 30 minutes the reaction mixture was filtered concentrated purified with silica gel column chromatography eluting with 8% methanol in dichloromethane to give a white solid (120, 4.20 g, 85.2%)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 2-chloro-4,5-difluoro-benzoic acid (118, 14.0 g, 0.0727 mol) in methanol (100 mL) was added sulfuric acid (concentrated, 98%, 2.00 mL, 0.0375 mol). The reaction was stirred at 60° C. for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (119, 13.0 g, 86.6%)