2-fluoro-6-hydroxybenzonitrile

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. followed by extraction The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution dried over sodium sulfate Finally, the solvent was distilled off in vacuo

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC. The mixture was cooled by slowly stirring to room temperature overnight the mixture was heated to 80° C the phases were separated the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water washed three times with 500 ml of methylene chloride Then, the combined organic phases were washed once with 10% strength hydrochloric acid The organic phase was dried over sodium sulfate Finally, the solvent was distilled off in vacuo

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. followed by extraction The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution dried over sodium sulfate Finally, the solvent was distilled off in vacuo

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC. The mixture was cooled by slowly stirring to room temperature overnight the mixture was heated to 80° C the phases were separated the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water washed three times with 500 ml of methylene chloride Then, the combined organic phases were washed once with 10% strength hydrochloric acid The organic phase was dried over sodium sulfate Finally, the solvent was distilled off in vacuo

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

実験手順: 6.3 g of chlorodifluoromethane were passed into a stirred mixture of 10.0 g of 2-hydroxy-6-fluorobenzonitrile, 50 ml of 1,2-dimethoxyethane and 25 ml of NaOH (33%) at 75° C. (the reflux condenser was cooled with dry ice), and stirring was continued for one hour at 70-75° C. After cooling, the batch was diluted with 300 ml of water and extracted three times using in each case 150 ml of tert-butyl methyl ether. After the solvent had been evaporated, 6.5 g of the desired product were obtained as an oil. After cooling extracted three times After the solvent had been evaporated

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

実験手順: 6.3 g of chlorodifluoromethane were passed into a stirred mixture of 10.0 g of 2-hydroxy-6-fluorobenzonitrile, 50 ml of 1,2-dimethoxyethane and 25 ml of NaOH (33%) at 75° C. (the reflux condenser was cooled with dry ice), and stirring was continued for one hour at 70-75° C. After cooling, the batch was diluted with 300 ml of water and extracted three times using in each case 150 ml of tert-butyl methyl ether. After the solvent had been evaporated, 6.5 g of the desired product were obtained as an oil. After cooling extracted three times After the solvent had been evaporated

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

実験手順: 7.8 g of 2-methoxy-6-fluorobenzonitrile and 18.0 g of pyridine hydrochloride were heated for 5 hours at 195° C. under dry nitrogen. After cooling, the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether, and the organic phase was subsequently extracted with 40 ml of 2N NaOH. The alkali extract was brought to pH 5 and subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether. After the solvent had been evaporated, 4.7 g of the desired product were obtained as an oil (HPLC: 93%). After cooling the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether the organic phase was subsequently extracted with 40 ml of 2N NaOH The alkali extract subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether After the solvent had been evaporated

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

実験手順: 7.8 g of 2-methoxy-6-fluorobenzonitrile and 18.0 g of pyridine hydrochloride were heated for 5 hours at 195° C. under dry nitrogen. After cooling, the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether, and the organic phase was subsequently extracted with 40 ml of 2N NaOH. The alkali extract was brought to pH 5 and subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether. After the solvent had been evaporated, 4.7 g of the desired product were obtained as an oil (HPLC: 93%). After cooling the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether the organic phase was subsequently extracted with 40 ml of 2N NaOH The alkali extract subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether After the solvent had been evaporated

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

実験手順: 7.8 g of 2-methoxy-6-fluorobenzonitrile and 18.0 g of pyridine hydrochloride were heated for 5 hours at 195° C. under dry nitrogen. After cooling, the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether, and the organic phase was subsequently extracted with 40 ml of 2N NaOH. The alkali extract was brought to pH 5 and subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether. After the solvent had been evaporated, 4.7 g of the desired product were obtained as an oil (HPLC: 93%). After cooling the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether the organic phase was subsequently extracted with 40 ml of 2N NaOH The alkali extract subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether After the solvent had been evaporated

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. 1H NMR (in CDCl3): δ=6.5-6.9 ppm (t, 1H, OCF2H), 7.15 ppm (m, 2H, arom. H), 7.65 ppm (m, 1H, arom. H). followed by extraction The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution dried over sodium sulfate Finally, the solvent was distilled off in vacuo

反応条件: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC. 1H NMR (in D6 dimethylsulfoxide): δ=6.85 ppm (m, 2H, arom. H), 7.55 ppm (q, 1H, arom. H), 11.7 ppm (s, 1H, OH). The mixture was cooled by slowly stirring to room temperature overnight the mixture was heated to 80° C the phases were separated the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water washed three times with 500 ml of methylene chloride Then, the combined organic phases were washed once with 10% strength hydrochloric acid The organic phase was dried over sodium sulfate Finally, the solvent was distilled off in vacuo

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

実験手順: 8.0 g (58.3 mmol) of 2-cyano-3-fluorophenol are dissolved in 100 ml of anhydrous toluene. With exclusion of moisture and under protective argon gas, a solution of 8.489 g (60 mmol) of chlorosulphonyl isocyanate is added dropwise, in the course of which slight exothermicity occurs. The mixture is stirred at 50° C. for 16 hours; phenol is no longer detectable by thin-layer chromatography. The mixture is heated under reflux for 16 hours; no further evolution of HCl gas takes place. The mixture is concentrated under reduced pressure, taken up in acetonitrile and admixed with aqueous acetonitrile. After stirring at room temperature for 1 hour, the mixture is concentrated, and the residue is dissolved in dichloromethane and washed with water. After drying and concentrating the organic phase, 13 g of a reaction mixture are obtained, which is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 1.3 g of a fraction are isolated, which consists of two components at log P=0.76 and 1.06. After separating this mixture by means of HPLC, 0.8 g of 4-amino-5-fluoro-1,2,3-benzoxathiazine 2,2-dioxide is obtained as a white solid. The mixture is heated under reflux for 16 hours The mixture is concentrated under reduced pressure After stirring at room temperature for 1 hour the mixture is concentrated the residue is dissolved in dichloromethane washed with water After drying concentrating the organic phase, 13 g of a reaction mixture are obtained which is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1 1.3 g of a fraction are isolated After separating this mixture by means of HPLC