2-chloro-4,5-difluorobenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 100 ml flange flask fitted with a distillation bridge and anchor stirrer, 14.5 g (0.25 mol) of potassium fluoride, 4.8 g (0.007 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 6.2 g (0.012 mol) of polyethylene glycol dimethyl ether 500 and 2.4 g (0.007 mol) of tetrabutylphosphonium bromide were introduced at 100° C. into the melt of 47.5 g (0.25 mol) of 2,4-dichloro-5-fluorobenzonitrile. Subsequently, 10 g (0.09 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 20 mbar and heating to 130° C. After the xylene had been distilled off, the reaction suspension was heated to 140° C. and stirred for 8 hours at this temperature. Amount of 2-chloro-4,5-difluorobenzonitrile formed: the reaction suspension was azeotropically dried by application of a vacuum of 20 mbar After the xylene had been distilled off the reaction suspension was heated to 140° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 100 ml flange flask fitted with a distillation bridge and anchor stirrer, 14.5 g (0.25 mol) of potassium fluoride, 4.8 g (0.007 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 6.2 g (0.012 mol) of polyethylene glycol dimethyl ether 500 and 2.4 g (0.007 mol) of tetrabutylphosphonium bromide were introduced at 100° C. into the melt of 47.5 g (0.25 mol) of 2,4-dichloro-5-fluorobenzonitrile. Subsequently, 10 g (0.09 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 20 mbar and heating to 130° C. After the xylene had been distilled off, the reaction suspension was heated to 140° C. and stirred for 8 hours at this temperature. Amount of 2-chloro-4,5-difluorobenzonitrile formed: the reaction suspension was azeotropically dried by application of a vacuum of 20 mbar After the xylene had been distilled off the reaction suspension was heated to 140° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.70 g (0.03 ) of 2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KF and 30 ml of dimethylsulfoxide, was reacted at a temperature of from 140° to 150° C. for 3.5 hours in a glass reactor. After completion of the reaction, the mixture was poured into ice water (50 ml) and extracted with chloroform. The chloroform extract was washed five times with water and then dried. Then chloroform was distilled off. The residue was distilled under reduced pressure to obtain 3.57 g (yield: 68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107° C./37 mmHg; melting point: 35°-37° C. After completion of the reaction extracted with chloroform The chloroform extract was washed five times with water dried Then chloroform was distilled off The residue was distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.70 g (0.03 ) of 2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KF and 30 ml of dimethylsulfoxide, was reacted at a temperature of from 140° to 150° C. for 3.5 hours in a glass reactor. After completion of the reaction, the mixture was poured into ice water (50 ml) and extracted with chloroform. The chloroform extract was washed five times with water and then dried. Then chloroform was distilled off. The residue was distilled under reduced pressure to obtain 3.57 g (yield: 68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107° C./37 mmHg; melting point: 35°-37° C. After completion of the reaction extracted with chloroform The chloroform extract was washed five times with water dried Then chloroform was distilled off The residue was distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 2-chloro-4,5-difluorobenzonitrile (240 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (390 mg) and lithium carbonate (152 mg), the title compound was obtained as a colorless solid (yield: 200 mg) by an operation similar to that in Example 3.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution (20 mL) of 2-chloro-4,5-difluorobenzoic acid (1.0 g) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.15 g) and N-hydroxysuccinimide (717 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 28% aqueous ammonia solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-chloro-4,5-difluorobenzamide as a colorless solid (yield: 760 mg, yield: 76%). To a solution (5 mL) of 2-chloro-4,5-difluorobenzamide (300 mg) in N,N-dimethylformamide was added pyridine (0.253 mL), and oxalyl chloride (0.20 mL) was added dropwise thereto under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (yield: 250 mg). was added dropwise under ice-cooling the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure