methyl 2-chloro-4-fluorobenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: Cyclopropylmethylamine (1.51 g) and potassium carbonate (1.46 g) were added to a solution of methyl 2-chloro-4-fluorobenzoate (1.00 g). The reaction mixture was stirred at room temperature for 6 hours and then heated with stirring at 100° C. for 6 hours under a microwave reactor. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.23 g). heated with stirring at 100° C. for 6 hours under a microwave reactor extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 2-chloro-4-fluorobenzoate (1.92 g, 10.2 mmol, 1 eq), cesium carbonate (3.74 g, 11.5 mmol, 0.13 eq) and benzyl mercaptan (1.3 g, 10.5 mmol, 1.03 eq) were combined in dimethyl sulphoxide (20 ml) and the reaction mixture heated at 50° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then washed with water (10 ml). The organic phase was dried over sodium sulphate, evaporated to yield the title compound as pink oil (2.82 g, 9.63 mmol, 95%). then washed with water (10 ml) The organic phase was dried over sodium sulphate evaporated

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-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C. was dropwise added at a temperature of below 10° C Precipitated crystals were collected by filtration washed with water

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

実験手順: To a stirred solution of 4.00 g (20.6 mmol) 2-chloro-4-fluoro-benzoic acid methyl ester (Apollo) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and is 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 product 1a was obtained in 99% yield (4.36 g, 20.4 mmol) and was used for the next step without purification. is 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

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

実験手順: To a stirred solution of 4.00 g (20.6 mmol) 2-chloro-4-fluoro-benzoic acid methyl ester (Apollo) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and is 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 product 1a was obtained in 99% yield (4.36 g, 20.4 mmol) and was used for the next step without purification. is 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

反応条件: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography

反応条件: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography