difluoromethanesulfonyl chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (47) was prepared by the following method: To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (20 mg, 0.052 mmol) in neat pyridine (1 mL) at 0° C. was added difluoromethanesulfonyl chloride (60 μL). After 3 d, the reaction was quenched with saturated aqueous ammonium chloride (1 mL) and then extracted with ethyl acetate (3×2 mL). The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) and concentrated to dryness to afford crude 2-(4-Bromophenyl)-5-cyclopropyl-6-{[(difluoromethyl)sulfonyl]amino}-N-methyl-2H-indazole-3-carboxamide (18 mg, 69%) which was used without further purification. Compound (47) was prepared by the following method the reaction was quenched with saturated aqueous ammonium chloride (1 mL) extracted with ethyl acetate (3×2 mL) The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) concentrated to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (47) was prepared by the following method: To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (20 mg, 0.052 mmol) in neat pyridine (1 mL) at 0° C. was added difluoromethanesulfonyl chloride (60 μL). After 3 d, the reaction was quenched with saturated aqueous ammonium chloride (1 mL) and then extracted with ethyl acetate (3×2 mL). The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) and concentrated to dryness to afford crude 2-(4-Bromophenyl)-5-cyclopropyl-6-{[(difluoromethyl)sulfonyl]amino}-N-methyl-2H-indazole-3-carboxamide (18 mg, 69%) which was used without further purification. Compound (47) was prepared by the following method the reaction was quenched with saturated aqueous ammonium chloride (1 mL) extracted with ethyl acetate (3×2 mL) The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) concentrated to dryness

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-indol-2-one (0.50 g) and 1-methyl-1H-imidazole (0.37 g) are introduced as initial charge in 5 ml of dichloromethane and cooled to −20° C. With stirring, difluoromethanesulfonyl chloride (0.58 g) is added dropwise and the mixture is slowly warmed to room temperature. The mixture is stirred for 3 hours at room temperature. HPLC analysis detects starting material (67%), the desired product (25%) and further components. The mixture is added to 10 ml of water, the phases are separated and the organic phase is concentrated by evaporation in vacuo. The residue is purified by chromatography and the product is separated off from the unreacted starting material. This gives the title compound in an HPLC purity of 86% (0.16 g, 22% of theory). By means of 2D-NMR, it is possible to confirm the structure as N-sulfonylated compound. the mixture is slowly warmed to room temperature The mixture is stirred for 3 hours at room temperature

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-indol-2-one (0.50 g) and 1-methyl-1H-imidazole (0.37 g) are introduced as initial charge in 5 ml of dichloromethane and cooled to −20° C. With stirring, difluoromethanesulfonyl chloride (0.58 g) is added dropwise and the mixture is slowly warmed to room temperature. The mixture is stirred for 3 hours at room temperature. HPLC analysis detects starting material (67%), the desired product (25%) and further components. The mixture is added to 10 ml of water, the phases are separated and the organic phase is concentrated by evaporation in vacuo. The residue is purified by chromatography and the product is separated off from the unreacted starting material. This gives the title compound in an HPLC purity of 86% (0.16 g, 22% of theory). By means of 2D-NMR, it is possible to confirm the structure as N-sulfonylated compound. the mixture is slowly warmed to room temperature The mixture is stirred for 3 hours at room temperature

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.47 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −15° C. with nitrogen. With stirring, difluoromethanesulfonyl chloride (0.62 g) is added dropwise in two portions and the mixture is heated to 10° C. in 2.5 hours. It is cooled to 0° C., 1-methyl-1H-imidazole (0.24 g) and difluoromethanesulfonyl chloride (0.35 g) are added, and the mixture is warmed to room temperature over the course of 3 hours, after-stirred for 4 hours and left to stand for 48 hours. For work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 91% (0.52 g, 39% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is heated to 10° C. in 2.5 hours It is cooled to 0° C. the mixture is warmed to room temperature over the course of 3 hours after-stirred for 4 hours left the mixture is stirred the solid is filtered off washed with dilute hydrochloric acid and water dried

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.66 g) is added dropwise in two portions and the mixture is stirred for 2.5 hours at −5 to −10° C. For the work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 99% (0.91 g, 70% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is stirred for 2.5 hours at −5 to −10° C the mixture is stirred the solid is filtered off washed with dilute hydrochloric acid and water dried

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.66 g) is added dropwise in two portions and the mixture is stirred for 2.5 hours at −5 to −10° C. For the work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 99% (0.91 g, 70% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is stirred for 2.5 hours at −5 to −10° C the mixture is stirred the solid is filtered off washed with dilute hydrochloric acid and water dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5,7-difluoro-1,3-dihydro-2H-indol-2-one (1.0 g), 1-methyl-1H-imidazole (0.74 g) and difluoromethanesulfonyl chloride (1.09 g) are reacted in 8 ml of dichloromethane analogously to Example 5. For the work-up, water is added and stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 97% (1.08 g, 82% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the solid is filtered off washed with dilute hydrochloric acid and water dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Diethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.46 g) is added dropwise and the mixture is after-stirred for 2 hours at 0° C. to 6° C. After adding 1-methyl-1H-imidazole (0.25 g) and difluoromethanesulfonyl chloride (0.23 g), the mixture is stirred for 2 hours at 0° C. to 10° C. After adding 5 ml of water, the mixture is adjusted to pH 2 using 10% strength hydrochloric acid, the organic solvent is largely distilled off in vacuo, and the solid is filtered off, washed with water and heptane and dried. This gives the title compound as a solid in an HPLC purity of 93% (1.19 g, 83% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is after-stirred for 2 hours at 0° C. to 6° C the mixture is stirred for 2 hours at 0° C. to 10° C the organic solvent is largely distilled off in vacuo the solid is filtered off washed with water and heptane dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Diethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 10 ml of dichloromethane and cooled to 0° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.46 g) is added dropwise and the mixture is after-stirred for 2 hours at 0° C. to 6° C. After adding 1-methyl-1H-imidazole (0.25 g) and difluoromethanesulfonyl chloride (0.23 g), the mixture is stirred for 2 hours at 0° C. to 10° C. After adding 5 ml of water, the mixture is adjusted to pH 2 using 10% strength hydrochloric acid, the organic solvent is largely distilled off in vacuo, and the solid is filtered off, washed with water and heptane and dried. This gives the title compound as a solid in an HPLC purity of 93% (1.19 g, 83% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is after-stirred for 2 hours at 0° C. to 6° C the mixture is stirred for 2 hours at 0° C. to 10° C the organic solvent is largely distilled off in vacuo the solid is filtered off washed with water and heptane dried

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-fluoro-1,3-dihydro-2H-indol-2-one (50 g) and 1-methyl-1H-imidazole (30.5 g) are introduced as initial charge in 430 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, a solution of difluoromethanesulfonyl chloride (41.8 g) in 70 ml of dichloromethane is added dropwise at −15° C. to −5° C. over the course of 30 minutes, and the mixture is after-stirred for 4 hours at −15° C. to 0° C. 1-Methyl-1H-imidazole (2.7 g) and difluoromethanesulfonyl chloride (4.9 g) are added to the reaction mixture and stirred for 2 hours at 0° C. With ice cooling, 300 ml of water are added to the reaction mixture, the mixture is after-stirred for 30 minutes and the organic solvent is largely distilled off in vacuo. The residue is filtered, the solid product is washed twice with 150 ml of water and twice with 40 ml of acetonitrile and dried. This gives the title compound as a solid in an HPLC purity of 96% (63.9 g, 95% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is after-stirred for 4 hours at −15° C. to 0° C stirred for 2 hours at 0° C the mixture is after-stirred for 30 minutes the organic solvent is largely distilled off in vacuo The residue is filtered the solid product is washed twice with 150 ml of water and twice with 40 ml of acetonitrile dried

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (10 g) and 1-methyl-1H-imidazole (5.4 g) are introduced as initial charge in 100 ml of dichloromethane and cooled to −5° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (7.03 g) is added dropwise at −5° C. to 0° C. over the course of 20 minutes, and the mixture is after-stirred at this temperature for 2.5 hours. The reaction mixture is admixed with 50 ml of water and mixed thoroughly. The organic solvent is largely distilled off in vacuo and the residue is filtered. The solid product is washed with water and acetonitrile and dried in a vacuum drying cabinet. This gives the title compound as a solid in an HPLC purity of 93% (12.5 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product. the mixture is after-stirred at this temperature for 2.5 hours mixed thoroughly The organic solvent is largely distilled off in vacuo the residue is filtered The solid product is washed with water and acetonitrile dried in a vacuum drying cabinet