methyl 2-methyl-1,1,4-trioxo-3H-1lambda6,2-benzothiazine-3-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A mixture consisting of 7.68 g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8 g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2 g of crystals having a melting point of 246°-248° C. (decomp.) were obtained in a 72.3% yield. formed by this reaction was continuously distilled off After the mixture was cooled the resulting precipitate was separated by filtration The filtrate was concentrated cooled to obtain an additional precipitate, which washed with hot chloroform were obtained in a 72.3% yield

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

実験手順: Methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (50 g.) is added to a solution of sodium hydroxide (160 g.) in water (500 ml.) at 70° C. The resulting lemon-yellow slurry is then heated at 90°-95° C. for 45 minutes and then cooled to room temperature is an ice-water bath. The pH of the reaction mixture is adjusted to 1-1.5 by gradual addition of concentrated hydrochloric acid (350 ml.). Ice chips are added as necessary to keep the temperature below 35° C. The acid product precipitates and is granulated by stirring at 10°-15° C. for 15 minutes. It is recovered by suction filtration, washed with water (100 ml.) and reslurried in water (250 ml.) for a half hour to remove excess hydrochloric acid. It is again filtered with suction and washed with water (100 ml.). Twenty-five grams of the wet filter cake (total wet filter cake is 25.5 g.) is dissolved in warm methanol (150 ml.), the solution filtered and water (50 ml.) added to the filtrate. The addition of seed crystals causes immediate precipitation of product. The slurry is granulated by stirring at about 10° C. for a half hour. The white crystalline product is separated by filtration, washed with water and air-dried. Yield = 13.2 g., M.p. 144°-146° C. The resulting lemon-yellow slurry is then heated at 90°-95° C. for 45 minutes Ice chips are added as necessary the temperature below 35° C The acid product precipitates It is recovered by suction filtration washed with water (100 ml.) reslurried in water (250 ml.) for a half hour to remove excess hydrochloric acid It is again filtered with suction washed with water (100 ml.) Twenty-five grams of the wet filter cake (total wet filter cake is 25.5 g.) is dissolved in warm methanol (150 ml.) the solution filtered water (50 ml.) added to the filtrate The addition of seed crystals precipitation of product by stirring at about 10° C. for a half hour The white crystalline product is separated by filtration washed with water air-dried

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a five liter flask equipped with thermometer, packed distillation column, condenser, and stirrer, under a nitrogen atmosphere is added 3300 ml mixed xylenes, 80 g (0.297 mole) methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mole) 2-aminopyridine and 8 g of activated carbon (Darco G-60* or Darco KBB*). The mixture is heated at reflux (ca. 140° C.) for 28 hours while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours, then at a rate of 5-10 ml per hour for the remaining reflux period, while adding fresh xylene to maintain a reaction volume of about 3500 ml. After 28 hours, the reaction mixture is cooled slightly (~100° C.) and filtered to remove carbon. The carbon cake was washed with warm xylene (100 ml), the filtrate and washings cooled slowly under a nitrogen atmosphere with rapid stirring to 25°-50° C. Stirring was continued for one hour to allow for complete crystallization. The crystals were collected by filtration, the mother liquor concentrated to about 1500 ml, cooled under nitrogen to 0°-5° C., filtered, the cake washed with 100 ml cold xylene and the crystals dried under vacuum below 60° C. for several hours. The yield is 76.7-84.6 g (78-86% of theory). Average throughput 24.4 g/liter of solvent. To a five liter flask equipped with thermometer, distillation column, condenser, and stirrer under a nitrogen atmosphere is added 3300 ml The mixture is heated while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours at a rate of 5-10 ml per hour for the remaining reflux period while adding fresh xylene to maintain a reaction volume of about 3500 ml the reaction mixture is cooled slightly (~100° C.) filtered to remove carbon The carbon cake was washed with warm xylene (100 ml) the filtrate and washings cooled slowly under a nitrogen atmosphere Stirring was continued for one hour to allow for complete crystallization The crystals were collected by filtration the mother liquor concentrated to about 1500 ml cooled under nitrogen to 0°-5° C. filtered the cake washed with 100 ml cold xylene the crystals dried under vacuum below 60° C. for several hours

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a five liter flask equipped with thermometer, packed distillation column, condenser, and stirrer, under a nitrogen atmosphere is added 3300 ml mixed xylenes, 80 g (0.297 mole) methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mole) 2-aminopyridine and 8 g of activated carbon (Darco G-60* or Darco KBB*). The mixture is heated at reflux (ca. 140° C.) for 28 hours while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours, then at a rate of 5-10 ml per hour for the remaining reflux period, while adding fresh xylene to maintain a reaction volume of about 3500 ml. After 28 hours, the reaction mixture is cooled slightly (~100° C.) and filtered to remove carbon. The carbon cake was washed with warm xylene (100 ml), the filtrate and washings cooled slowly under a nitrogen atmosphere with rapid stirring to 25°-50° C. Stirring was continued for one hour to allow for complete crystallization. The crystals were collected by filtration, the mother liquor concentrated to about 1500 ml, cooled under nitrogen to 0°-5° C., filtered, the cake washed with 100 ml cold xylene and the crystals dried under vacuum below 60° C. for several hours. The yield is 76.7-84.6 g (78-86% of theory). Average throughput 24.4 g/liter of solvent. To a five liter flask equipped with thermometer, distillation column, condenser, and stirrer under a nitrogen atmosphere is added 3300 ml The mixture is heated while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours at a rate of 5-10 ml per hour for the remaining reflux period while adding fresh xylene to maintain a reaction volume of about 3500 ml the reaction mixture is cooled slightly (~100° C.) filtered to remove carbon The carbon cake was washed with warm xylene (100 ml) the filtrate and washings cooled slowly under a nitrogen atmosphere Stirring was continued for one hour to allow for complete crystallization The crystals were collected by filtration the mother liquor concentrated to about 1500 ml cooled under nitrogen to 0°-5° C. filtered the cake washed with 100 ml cold xylene the crystals dried under vacuum below 60° C. for several hours

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

実験手順: A mixture consisting of 7.68 g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8 g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2 g of crystals having a melting point of 246°-248° C. (decomp.) were obtained in a 72.3% yield. formed by this reaction was continuously distilled off After the mixture was cooled the resulting precipitate was separated by filtration The filtrate was concentrated cooled to obtain an additional precipitate, which washed with hot chloroform were obtained in a 72.3% yield

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

実験手順: A mixture consisting of 7.68 g (0.0285 mole) of methyl 3,4-dihydro-2-methyl-4-oxo-2H-benzothiazine-3-carboxylate 1,1-dioxide, 4.8 g (0.0428 mole) of 2-amino-6-fluoropyridine, and 29 ml of xylene was refluxed for 17 hours, during which the methanol formed by this reaction was continuously distilled off. After the mixture was cooled by allowing it to stand overnight, the resulting precipitate was separated by filtration. The filtrate was concentrated and then cooled to obtain an additional precipitate, which was combined with the previously obtained precipitate and washed with hot chloroform. Thus, 7.2 g of crystals having a melting point of 246°-248° C. (decomp.) were obtained in a 72.3% yield. formed by this reaction was continuously distilled off After the mixture was cooled the resulting precipitate was separated by filtration The filtrate was concentrated cooled to obtain an additional precipitate, which washed with hot chloroform were obtained in a 72.3% yield

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8.1 g of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 5.7 g of 4-methyl-7-amino-coumarin are dissolved in 280 ml of xylene and the solution is heated for 21/2 hours in a bath of 170° C. to distill off the methanol formed during the reaction. The reaction mixture is refluxed for a further 5 hours, cooled, and the precipitate is collected by filtration. The precipitate is digested with 100 ml of 2N-hydrochloric acid at elevated temperature, treated with 100 ml of chloroform and extracted. The residue is collected by suction, washed successively with water, ethanol, methylene chloride and diethyl ether, washed, and dried, affording 2-methyl-3,4-dihydro-4-oxo-N-(2-oxo-4-methyl-2H-1-benzopyran-7-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide with a melting point above 285° C. to distill off the methanol formed during the reaction The reaction mixture is refluxed for a further 5 hours cooled the precipitate is collected by filtration treated with 100 ml of chloroform extracted The residue is collected by suction washed successively with water, ethanol, methylene chloride and diethyl ether washed dried

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a five liter flask equipped with thermometer, packed distillation column, condenser, and stirrer, under a nitrogen atmosphere is added 3300 ml mixed xylenes, 80 g (0.297 mole) methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mole) 2-aminopyridine and 8 g of activated carbon (Darco G-60* or Darco KBB*). The mixture is heated at reflux (ca. 140° C.) for 28 hours while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours, then at a rate of 5-10 ml per hour for the remaining reflux period, while adding fresh xylene to maintain a reaction volume of about 3500 ml. After 28 hours, the reaction mixture is cooled slightly (~100° C.) and filtered to remove carbon. The carbon cake was washed with warm xylene (100 ml), the filtrate and washings cooled slowly under a nitrogen atmosphere with rapid stirring to 25°-50° C. Stirring was continued for one hour to allow for complete crystallization. The crystals were collected by filtration, the mother liquor concentrated to about 1500 ml, cooled under nitrogen to 0°-5° C., filtered, the cake washed with 100 ml cold xylene and the crystals dried under vacuum below 60° C. for several hours. The yield is 76.7-84.6 g (78-86% of theory). Average throughput 24.4 g/liter of solvent. To a five liter flask equipped with thermometer, distillation column, condenser, and stirrer under a nitrogen atmosphere is added 3300 ml The mixture is heated while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours at a rate of 5-10 ml per hour for the remaining reflux period while adding fresh xylene to maintain a reaction volume of about 3500 ml the reaction mixture is cooled slightly (~100° C.) filtered to remove carbon The carbon cake was washed with warm xylene (100 ml) the filtrate and washings cooled slowly under a nitrogen atmosphere Stirring was continued for one hour to allow for complete crystallization The crystals were collected by filtration the mother liquor concentrated to about 1500 ml cooled under nitrogen to 0°-5° C. filtered the cake washed with 100 ml cold xylene the crystals dried under vacuum below 60° C. for several hours

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8.1 g of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 5.7 g of 4-methyl-7-amino-coumarin are dissolved in 280 ml of xylene and the solution is heated for 21/2 hours in a bath of 170° C. to distill off the methanol formed during the reaction. The reaction mixture is refluxed for a further 5 hours, cooled, and the precipitate is collected by filtration. The precipitate is digested with 100 ml of 2N-hydrochloric acid at elevated temperature, treated with 100 ml of chloroform and extracted. The residue is collected by suction, washed successively with water, ethanol, methylene chloride and diethyl ether, washed, and dried, affording 2-methyl-3,4-dihydro-4-oxo-N-(2-oxo-4-methyl-2H-1-benzopyran-7-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide with a melting point above 285° C. to distill off the methanol formed during the reaction The reaction mixture is refluxed for a further 5 hours cooled the precipitate is collected by filtration treated with 100 ml of chloroform extracted The residue is collected by suction washed successively with water, ethanol, methylene chloride and diethyl ether washed dried

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8.1 g of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 5.7 g of 4-methyl-7-amino-coumarin are dissolved in 280 ml of xylene and the solution is heated for 21/2 hours in a bath of 170° C. to distill off the methanol formed during the reaction. The reaction mixture is refluxed for a further 5 hours, cooled, and the precipitate is collected by filtration. The precipitate is digested with 100 ml of 2N-hydrochloric acid at elevated temperature, treated with 100 ml of chloroform and extracted. The residue is collected by suction, washed successively with water, ethanol, methylene chloride and diethyl ether, washed, and dried, affording 2-methyl-3,4-dihydro-4-oxo-N-(2-oxo-4-methyl-2H-1-benzopyran-7-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide with a melting point above 285° C. to distill off the methanol formed during the reaction The reaction mixture is refluxed for a further 5 hours cooled the precipitate is collected by filtration treated with 100 ml of chloroform extracted The residue is collected by suction washed successively with water, ethanol, methylene chloride and diethyl ether washed dried