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In a 500 ml flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-carbaldehyde are added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37 C. After the end of the addition, the reaction mixture is stirred at 50 C for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 ml of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-carboxylic acid as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1 H, JHF = 53.60 Hz)13.19 (s, 1 H); IR (KBr) : 1688 cm"1 (C=0); 2200-3200 cm"1 broad (hydrogen bond). |
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Synthesis of S-chloro-S-CdifluoromethylVI -methyl-I H-pyrazole^-carboxylic acid (example llla-1) In a 500 ml flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4- carbaldehyde are added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37 C. After the end of the addition, the reaction mixture is stirred at 50 C for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 ml of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-carboxylic acid as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1 H, JHF = 53.60 Hz);13.19 (s, 1 H); IR (KBr) : 1688 cm"1 (C=0); 2200-3200 cm"1 broad (hydrogen bond). |
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In a 500 mL flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4- carbaldehyde are added to 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6ml of water is added to the reaction mixture, followed by 103 mL of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37 C. After the end of the addition, the reaction mixture is stirred at 50 C for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 mL of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 mL of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-carboxylic acid as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1 H, JHF = 53.60 Hz); 13.19 (s, 1 H); IR (KBr) : 1688 cm"1 (C=0); 2200-3200 cm"1 broad (hydrogen bond). |
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5-Chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (Example lib); (lla) (lib)In a 500 mL round-bottom flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-l-methyl-lH- pyrazole-4-carbaldehyde were taken up in 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 mL of water was added to the reaction mixture, followed by 103 mL of a 30% strength solution of hydrogen peroxide in water. During the addition, the temperature was kept below 37 C. The reaction mixture was then stirred at 50 C for 7 h. After cooling, the organic phase was extracted with 100 mL of water. The aqueous phase was acidified to pH 2 using dilute hydrochloric acid. The white precipitate formed was filtered off, washed twice with 20 mL of water and dried. This gave 3.2 g of 5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid as a white solid.¾ NMR (400 MHz, DMSO- 6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1H, JHF= 53.60 Hz); 13.19 (s, 1H); IR (KBr): 1688 cm_1 (C=0); 2200-3200 cm"1 broad; |
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Synthesis of 5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (example Vb-1); In a 500 ml flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4- carbaldehyde were added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6ml of water was added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37C. After the end of the addition, the reaction mixture was stirred at 50C for 7 hours. Once the reaction mixture was back to room temperature, the two phases were separated and the organic phase was extracted with 100 ml of water. The combined aqueous phases were acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate was filtered, washed with 2*20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-l-methyl-lH- pyrazole-4-carboxylic acid as a white solid.'H NMR (400 MHz, DMSO- 6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1H, JHF= 53.60 Hz)13.19 (s, 1H);IR (KBr) : 1688 cm"1 (C=0); 2200-3200 cm"1 broad (hydrogen bond); |
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In a 500 mL round-bottom flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H- pyrazole-4-carbaldehyde were taken up in 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 mL of water was added to the reaction mixture, followed by 103 mL of a 30% strength solution of hydrogen peroxide in water. During the addition, the temperature was kept below 37 C. The reaction mixture was then stirred at 50 C for 7 h. After cooling, the organic phase was extracted with 100 mL of water. The aqueous phase was acidified to pH 2 using dilute hydrochloric acid. The white precipitate formed was filtered off, washed twice with 20 mL of water and dried. This gave 3.2 g of 5-chloro-3-(difluoromethyl)-1 -methyl-1 H-pyrazole-4-carboxylic acid as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1 H, JHF = 53.60 Hz); 13.19 (s, 1 H); IR (KBr): 1688 cm"1 (C=0); 2200-3200 cm"1 broad; |
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5-Chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (Example lib) (I la) (Mb)In a 500 mL round-bottom flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-l-methyl-lH- pyrazole-4-carbaldehyde were taken up in 30 mL of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 mL of water was added to the reaction mixture, followed by 103 mL of a 30% strength solution of hydrogen peroxide in water. During the addition, the temperature was kept below 37 C. The reaction mixture was then stirred at 50 C for 7 h. After cooling, the organic phase was extracted with 100 mL of water. The aqueous phase was acidified to pH 2 using dilute hydrochloric acid. The white precipitate formed was filtered off, washed twice with 20 mL of water and dried. This gave 3.2 g of 5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid as a white solid.'H NMR (400 MHz, DMSO- 6) delta ppm : 3.78 (s, 3H); 7.12 (t, 1H, JHF= 53.60 Hz); 13.19 (s, IR (KBr): 1688 cm_1 (C=0); 2200-3200 cm"1 broad; |
| 3.2 g |
With dihydrogen peroxide; sodium hydroxide; In water; toluene; at 37 - 50℃; for 7.0h; |
In a 500 ml flask, 6.0 g (31 mmol) of <strong>[660845-30-7]5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde</strong> are added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37 C. After the end of the addition, the reaction mixture is stirred at 50 C. for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 ml of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm: 3.78 (s, 3H); 7.12 (t, 1H, JHF=53.60 Hz); 13.19 (s, 1H); IR (KBr): 1688 cm-1 (C=O); 2200-3200 cm-1 broad (hydrogen bond). |
| 40 g |
With copper(II) oxide; sodium hydroxide; In water; at 25 - 30℃; for 15.0h; |
In 1000 mL reaction flask, 38.9g 3- difluoromethyl-1-methyl-5-chloro-4-carbaldehyde and 390ml of water, 8.4g of sodium hydroxide was added, followed by stirring, 1g of nano copper oxide, control of the reaction temperature is 25-30 C, air through an oxidation reaction 15 hours, starting material HPLC i.e.3- difluoromethyl-1-methyl-5-chloro-4-carbaldehyde , less than the total amount of an amount of 0.2%; the reaction was stopped by filtration, recovery of copper catalyst. The reaction mixture was cooled to below 10 C, add 31% hydrochloric acid to a pH of 1-2, the precipitated solid was filtered; the solid was washed with a small amount of water; and dried to give the product 3-methyl-5-fluoro-1- chloro-pyrazole-4-carboxylic acid 40g, HPLC content 99%; LC-MS: m / e = 210. |
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