2-methyl-1,2,6-thiadiazinane 1,1-dioxide

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

実験手順: To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.300 g, 0.80 mmol), 2-methyl-1,2,6-thiadiazinane 1,1-dioxide (0.144 g, 0.96 mmol) and Cu2O (0.086 g, 0.60 mmol) in pyridine (6.0 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.5 g) in water (25 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization. at reflux for 16 hr The reaction was filtered the solids washed with CHCl3 (100 mL) The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air The organic extracts were dried (MgSO4) the solvent evaporated in vacuo The residue was purified by preparative HPLC (Gilson semi preparative HPLC system a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min)

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

実験手順: To a solution of N-methyl-1,3-diaminopropane (37.6 mL, 312 mmol) and sulfamide (10.0 g, 104 mmol) were heated at reflux for 16 hr. The solvent was evaporated in vacuo and the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as an oil. at reflux for 16 hr The solvent was evaporated in vacuo the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1)

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

実験手順: To a solution of N-methyl-1,3-diaminopropane (37.6 mL, 312 mmol) and sulfamide (10.0 g, 104 mmol) were heated at reflux for 16 hr. The solvent was evaporated in vacuo and the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as an oil. at reflux for 16 hr The solvent was evaporated in vacuo the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1)

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

実験手順: A mixture comprising 30 g (312 mmol) of sulfamide, 27.5 g (312 mmol) of N-methyl-1,3-propanediamine and 300 ml of dry pyridine was refluxed overnight at 130° C. The mixture was left to cool, and then pyridine was distilled off under reduced pressure. To the residue, 200 ml of chloroform was added and insoluble substance was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3) and then subjected to distillation under reduced pressure to obtain 36.2 g of 2-methyl-tetrahydro-1,2,6-thiadiazine-1,1-dioxide (boiling point: 130°-133° C./0.23 mmHg). The mixture was left to cool pyridine was distilled off under reduced pressure To the residue, 200 ml of chloroform was added insoluble substance was filtered off The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (CHCl3) subjected to distillation under reduced pressure

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

実験手順: A mixture comprising 30 g (312 mmol) of sulfamide, 27.5 g (312 mmol) of N-methyl-1,3-propanediamine and 300 ml of dry pyridine was refluxed overnight at 130° C. The mixture was left to cool, and then pyridine was distilled off under reduced pressure. To the residue, 200 ml of chloroform was added and insoluble substance was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3) and then subjected to distillation under reduced pressure to obtain 36.2 g of 2-methyl-tetrahydro-1,2,6-thiadiazine-1,1-dioxide (boiling point: 130°-133° C./0.23 mmHg). The mixture was left to cool pyridine was distilled off under reduced pressure To the residue, 200 ml of chloroform was added insoluble substance was filtered off The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (CHCl3) subjected to distillation under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of N-methyl-1,3-diaminopropane (1.70 mL, 16.3 mmol) in pyridine (20 mL) was added sulfamide (1.877 g, 19.5 mmol). The mixture was heated in an oil bath at 120° C. for 16 hrs. After cooling to room temperature, the mixture was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium chloride. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate, filtered, and concentrated to afford a colorless oil (1.3 g, 53%). 1H NMR (300 MHz, CDCl3) δ 4.11 (br s, 1H), 3.60-3.48 (m, 2H), 3.32 (t, 2H, J=5.7 Hz), 2.78 (s, 3H), 1.85-1.72 (m, 2H). After cooling to room temperature the mixture was concentrated the residue partitioned between ethyl acetate and saturated aqueous sodium chloride The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium chloride dried (anhydrous sodium sulfate filtered concentrated

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

実験手順: To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.300 g, 0.80 mmol), 2-methyl-1,2,6-thiadiazinane 1,1-dioxide (0.144 g, 0.96 mmol) and Cu2O (0.086 g, 0.60 mmol) in pyridine (6.0 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.5 g) in water (25 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization. at reflux for 16 hr The reaction was filtered the solids washed with CHCl3 (100 mL) The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air The organic extracts were dried (MgSO4) the solvent evaporated in vacuo The residue was purified by preparative HPLC (Gilson semi preparative HPLC system a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min)

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

実験手順: To a solution of N-methyl-1,3-diaminopropane (37.6 mL, 312 mmol) and sulfamide (10.0 g, 104 mmol) were heated at reflux for 16 hr. The solvent was evaporated in vacuo and the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1) to afford the title compound as an oil. at reflux for 16 hr The solvent was evaporated in vacuo the residue was purified by chromatography (SiO2, EtOAc/CH2Cl2: 1:1)

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

実験手順: A mixture comprising 30 g (312 mmol) of sulfamide, 27.5 g (312 mmol) of N-methyl-1,3-propanediamine and 300 ml of dry pyridine was refluxed overnight at 130° C. The mixture was left to cool, and then pyridine was distilled off under reduced pressure. To the residue, 200 ml of chloroform was added and insoluble substance was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3) and then subjected to distillation under reduced pressure to obtain 36.2 g of 2-methyl-tetrahydro-1,2,6-thiadiazine-1,1-dioxide (boiling point: 130°-133° C./0.23 mmHg). The mixture was left to cool pyridine was distilled off under reduced pressure To the residue, 200 ml of chloroform was added insoluble substance was filtered off The solvent was distilled off under reduced pressure the residue was purified by silica gel column chromatography (CHCl3) subjected to distillation under reduced pressure