5-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde

41.6 g (270.1 mmoles) of phosphorus oxychloride was added, with ice-cooling, to 7.9 g (108.0 mmoles) of N, N-dimethylformamide. REFERENCE EXAMPLE 35 Production of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde; 41.6 g (270.1 mmoles) of phosphorus oxychloride was added, with ice-cooling, to 7.9 g (108.0 mmoles) of N, N-dimethylformamide. Thereto was added, at room temperature, 8.0 g (54.0 mmoles) of 3-difluoromethyl-1-methyl-1H-pyrazol-5-ol. The mixture was refluxed for 4 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water, a 5percent aqueous sodium hydroxide solution and water in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 7.7 g (yield: 73.3percent) of 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboaldehyde as white crystals. 75-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (II-1) To a solution of 137.5 g (929 mmol) of 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol (IX-1) in 136 ml (1858 mmol) of absolute dimethylformamide and 750 ml of toluene was added 571 g (3716 mmol) of phosphoryl chloride by dropwise addition with cooling. The reaction mixture was refluxed for 3 hours, cooled down and carefully poured into 4 L of ice-water. After extracting three times with 1500 mL of ethyl acetate each time, the combined organic phases were washed twice with saturated sodium bicarbonate solution and finally with saturated sodium chloride solution, dried over sodium sulphate and concentrated to obtain 129.2 g (72percent of theory having a purity of >99percent (GC)) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (II-1) in the form of a reddish brown solid which was used in the next reaction step without further purification.To a solution of 137.5 g (929 mmol) of 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol in 136 ml (1858 mmol) of dimethylformamide and 750 ml of toluene was added dropwise with cooling 571 g (3716 mmol) of phosphoryl chloride. The mixture was heated for 3 hours under reflux and allowed to cool, and the reaction mixture wash carefully poured into 41 of ice water. The product was extracted three times, each time with 1500 ml of ethyl acetate, and the combined organic phases were washed twice with saturated sodium bicarbonate solution and finally with saturated sodium chloride solution, dried over sodium sulphate and concentrated. 138 g (with a purity of >99percent (GC)) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (II-1) in the form of a yellow-brown solid was obtained, which was used without further purification in the next reaction step.Anhydrous 34 ml of N, N-dimethylformamide was added to a 250 ml three-necked flask, The system was cooled to 0 ° C, Then, 143 g of phosphorus oxychloride was added dropwise with stirring, About 2h plus finished, Stirring was continued for 30 minutes, 30 g of 1-methyl-3-difluoromethyl-5-hydroxy-1H-pyrazole obtained in step (1)Slowly warm to room temperature stirring 2h, And then the system temperature to 90 reaction 3h, Cooled to room temperature, Add to 1000ml of ice water, Extracted with ethyl acetate, The ethyl acetate was dried over anhydrous magnesium sulfate, Ethyl acetate was evaporated to give 36 g of a brown solid.The resulting brown solid was 1-methyl-3-(difluoromethyl)-5-chloro-1H-pyrazole-4-carbaldehyde, Do not use purification directly for the next step.Step2:DMF (9.5 mL, 0.12 mol) was stirred over ice bath and phosphoryl chloride (24.0 mL, 0.257 mol) was added dropwise. To the solution was added 3-(difluoromethyl)-l- methyl-lH-pyrazol-5(4H)-one (5.51 g, 0.0372 mol) portion wise and the mixture was heated at 120 °C for 40 minutes. The reaction mixture was cooled, and the phosphoryl chloride was quenched by adding small chunks of ice slowly with stirring. The mixture was then extracted with ethyl acetate three times and combined organic layer was washed with water and brine, dried over MgS04 and evaporated to give 5- chloro-3-(difluoromethyl)-l -methyl- lH-pyrazole-4-carbaldehyde (5.66 g, 78.2percent) as a dark orange/brown solid. This material was used without further purification for the next reaction.Ethyl difluoroacetoacetate (5.00 g, 30.1 mmol) was dissolved in anhydrous ethanol (100 mL), and the obtained mixture was stirred at 0 C, then hydrazine hydrate (1.45 g, 45.2 mmol) was added slowly into the mixture. After addition, the mixture was stirred at room temperature for 4 h, then heated to 80 C and stirred overnight, then the reaction was stopped. Ethanol was removed, and the residue was washed with water (50 mL), and then extracted with ethyl acetate (50 mL) three times. The combined organic layers were concentrated in vacuo to remove the solvent and give the product as a light yellow solid. DMF (2.20 g, 30.1 mmol) was stirred at 0 C, then phosphorus oxychloride (13.8 g, 90.3 mmol) was added slowly into DMF. After addition, the mixture was warmed to room temperature and stirred, then to the mixture was added the previously obtained light yellow solid. The above mixture was heated to 110 C and refluxed overnight. After the reaction was completed, the reaction mixture was washed with water (50 mL), and extracted with ethyl acetate (50 mL) three times. The combined organic layers were concentrated in vacuo to remove the solvent and give the product as a reddish brown solid. The above reddish brown solid and potassium carbonate (4.16 g, 30.1 mmol) were dissolved in DMF (50 mL), and the mixture was stirred at room temperature, then iodomethane (2.14 g, 15.1 mmol) was added into the above mixture. After addition, the mixture was heated to 80 C and stirred for 12 h. After the reaction was completed, the mixture was washed with water (50 mL), and extracted with ethyl acetate (50 mL) three times. The combined organic layers were concentrated in vacuo to remove the solvent, and the residue was purified by cholumn chromatography (eluent: Petroleum ether/EtOAc (v/v) = 10/1) to give colorless transparent liquids In an autoclave, 10 g of

Molecular Weight:194.56
XLogP3:1.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:194.0058468
Monoisotopic Mass:194.0058468
Topological Polar Surface Area:34.9
Heavy Atom Count:12
Complexity:181
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes