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Example 1; Sulfinylation of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with triethylamine hydrochloride, sodium trifluoromethylsulfinate and thionylchloride, in 6.5 molar equivalents of tolueneWithin a 3-neck, 50 ml. round bottom flask equipped with a magnetic stirrer bar and a thermometer were placed vacuum dried sodium trifluoromethylsulfinate (4.29 g, 27.5 mmol), vacuum dried triethylamine hydrochloride (5.16 g, 37.5 mmol), and 13 ml. an- hydrous toluene (6.5 molar equivalents relative to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H-pyrazole-3-carbonitrile) under an argon atmosphere. After cooling to 00C to 5 0C with an ice bath, thionylchloride (3.57 g, 30 mmol) was added slowly while keeping the reaction temperature below 5 0C. After stirring for another 30 min, vacuum dried 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-1 H-pyrazole-3- carbonitrile (8.03 g, 25 mmol, 99 % purity) was added at 5 0C, and the reaction mixture was heated to 50 0C within 5 min by a preheated water bath. The temperature of 50 0C was kept for another 6 hours before quenching the reaction with 50 ml. of saturated NaHCO3 solution. The resulting suspension was diluted with 30 ml. of ethylacetate. After phase separa- tion the organic layer was washed once with saturated NaHCtheta3 solution and concentrated under reduced pressure until dryness. The crude product was crystallized from refluxing toluene (100 g) affording the title compound as a white crystalline powder (8.06 g, 70 % yield, 94 % purity by quantitative HPLC). 1H-NMR (Bruker DRX-500, d6- DMSO): delta [ppm]: 8.33 (s), 7.57 (s).; Example 2; Sulfinylation of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with triethylamine hydrochloride, potassium trifluoromethylsulfinate and thionylchlorideWithin a 3-neck, 50 ml. round bottom flask equipped with a magnetic stirrer bar and a thermometer were placed vacuum dried potassium trifluoromethylsulfinate (4.73 g, 27.5 mmol), vacuum dried triethylamine hydrochloride (5.16 g, 37.5 mmol), thionylchloride (3.57 g, 30 mmol), and 15 ml. anhydrous toluene under an argon atmosphere. The reaction is further conducted as described above for example 1. EPO <DP n="25"/>The crude product was crystallized from refluxing chlorobenzene (100 g) affording the title compound as a white crystalline powder (7.44 g, 66 % yield, 96 % purity by quantitative HPLC). 1H-NMR (Bruker DRX-500, d6-DMSO): delta [ppm]: 8.33 (s), 7.57 (s).; Example 10; Sulfinylation of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with triethylamine hydrochloride, potassium trifluoromethylsulfinate and thionylchloride, in 4.5 molar equivalents of tolueneWithin a 3-neck, 50 mL round bottom flask equipped with a magnetic stirrer bar and a thermometer were placed vacuum dried potassium trifluoromethylsulfinate (5.16 g, 30 mmol), vacuum dried triethylamine hydrochloride (5.16 g, 37.5 mmol), and 10.4 g anhydrous toluene (4.5 molar equivalents relative to 5-amino-1-[2,6-dichloro-4- (trifluoromethyl)phenyl]-1 H-pyrazole-3-carbonitrile) under an argon atmosphere. After cooling to 00C to 5 0C with external cooling, thionylchloride (3.57 g, 30 mmol) was EPO <DP n="28"/>added within 15 min while keeping the reaction temperature below 5 0C. After stirring for another 30 min, vacuum dried 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-1 H- pyrazole-3-carbonitrile (8.03 g, 25 mmol, 99 % purity) was added at 5 0C, and the reaction mixture was kept at 5 0C for 60 min and then heated to 35 0C within 45 min. The temperature of 35 0C was kept for 3 hours before adding 4.6 g of toluene. After another 7 hours at 35 0C the reaction was quenched with 20 g of sodium hydroxide solution (10 wt.%).The resulting suspension was diluted with 30 ml. of ethylacetate. After phase separation the organic layer was washed once with sodium hydroxide solution (10 wt.%). After phase separation, the organic layer was analyzed by quantitative HPLC (80.4 % yield). The crude product was crystallized from a mixture of ethylacetate and toluene affording the title compound as a white crystalline powder (7.98 g, 73 % yield, 98 % purity by quantitative HPLC).; Example 11; Sulfinylation of 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with thionylchloride, triethylamine hydrochloride and dosage of potassium trifluoromethylsulfinateWithin a 750 mL reactor with a mechanical stirrer and a thermometer were placed vac- uum dried triethylamine hydrochloride (51.1 g, 368 mmol), 147 g anhydrous toluene(6.5 molar equivalents relative to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile), and thionylchloride (35.7 g, 294 mmol) under an argon atmosphere. After cooling to 00C to 5 0C with external cooling, vacuum dried potassium trifluoromethylsulfinate (50.4 g, 296 mmol) was added in three equal portions every 10 min while keeping the reaction temperature be... |
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Example 11; Sulfinylation of 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with thionylchloride, triethylamine hydrochloride and dosage of potassium trifluoromethylsulfinateWithin a 750 mL reactor with a mechanical stirrer and a thermometer were placed vac- uum dried triethylamine hydrochloride (51.1 g, 368 mmol), 147 g anhydrous toluene(6.5 molar equivalents relative to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile), and thionylchloride (35.7 g, 294 mmol) under an argon atmosphere. After cooling to 00C to 5 0C with external cooling, vacuum dried potassium trifluoromethylsulfinate (50.4 g, 296 mmol) was added in three equal portions every 10 min while keeping the reaction temperature below 5 0C. After stirring for another 30 min, vacuum dried 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-1 H-pyrazole-3- carbonitrile (79.5 g, 245 mmol, 99 % purity) was added at 5 0C, and the reaction mixture was kept at 5 0C for 60 min and then heated to 35 0C within 45 min. The temperature of 35 0C was kept for another 10 hours before quenching the reaction with 200 g of sodium hydroxide solution (10 wt.%).The resulting suspension was diluted with 176 mL of ethylacetate. After phase separation the organic layer was washed once with sodium hydroxide solution (10 wt.%). After phase separation, the organic layer was analyzed by quantitative HPLC (79 % yield). The content of compound F was below 2.9 weight percent in the crude mixture (without solvent). The product was crystallized from a mixture of ethylacetate and toluene affording the title compound as a white crystalline powder (77.1 g, 75 % yield, 98 % purity by quantitative HPLC).; These experiments Ca and Cb where compared to examples 18 and 19, which were conducted as described above for example 11 , employing potassium trifluoromethyl- sulfinate / pyridine hydrochloride / SOCb and potassium trifluoromethylsulfinate / trimethylamine hydrochloride / SOCb as reagents. |
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Example 11; Sulfinylation of 5-amino-1 -[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile with thionylchloride, triethylamine hydrochloride and dosage of potassium trifluoromethylsulfinateWithin a 750 mL reactor with a mechanical stirrer and a thermometer were placed vac- uum dried triethylamine hydrochloride (51.1 g, 368 mmol), 147 g anhydrous toluene(6.5 molar equivalents relative to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1 H- pyrazole-3-carbonitrile), and thionylchloride (35.7 g, 294 mmol) under an argon atmosphere. After cooling to 00C to 5 0C with external cooling, vacuum dried potassium trifluoromethylsulfinate (50.4 g, 296 mmol) was added in three equal portions every 10 min while keeping the reaction temperature below 5 0C. After stirring for another 30 min, vacuum dried 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-1 H-pyrazole-3- carbonitrile (79.5 g, 245 mmol, 99 % purity) was added at 5 0C, and the reaction mixture was kept at 5 0C for 60 min and then heated to 35 0C within 45 min. The temperature of 35 0C was kept for another 10 hours before quenching the reaction with 200 g of sodium hydroxide solution (10 wt.%).The resulting suspension was diluted with 176 mL of ethylacetate. After phase separation the organic layer was washed once with sodium hydroxide solution (10 wt.%). After phase separation, the organic layer was analyzed by quantitative HPLC (79 % yield). The content of compound F was below 2.9 weight percent in the crude mixture (without solvent). The product was crystallized from a mixture of ethylacetate and toluene affording the title compound as a white crystalline powder (77.1 g, 75 % yield, 98 % purity by quantitative HPLC).; These experiments Ca and Cb where compared to examples 18 and 19, which were conducted as described above for example 11 , employing potassium trifluoromethyl- sulfinate / pyridine hydrochloride / SOCb and potassium trifluoromethylsulfinate / trimethylamine hydrochloride / SOCb as reagents. |
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