N-(4-chlorophenyl)-4-fluorobenzenesulfonamide

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

Procedure: To a suspention of NaH (100 mmol, 55-65% in oil) in dry dioxane (140 mL) was added 3-dimethylamino-1-propanol (11.90 mL, 100 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (9.53 g, 33.35 mmol, preparation described in example 66) in dry dioxane (35 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (75 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×100 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. N-(4-chlorophenyl)-4-[3-(dimethylamino)propoxy]benzenesulfonamide was obtained as a colorless oil, in 96% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification. The resulting mixture was heated 24 h at 100° C Solvents were evaporated NH4Cl saturated solution in water (75 mL) was added the desired product was extracted with three portions of ethyl acetate (3×100 mL) Combined organic phases were dried over magnesium sulfate before filtering removal of solvent

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2aminoethyl)morpholine (293 μL, 2.25 mmol) was dissolved in THF (7.5 mL) and was cooled down to −78° C. A 2.5N solution of nBuLi in hexane (1 mL, 2.5 mmol) was added dropwise. After 5 min. at −78° C., the mixture was stirred 1 h at −40° C. N-aryl-benzenesulfonamide building block XIII, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (214 mg, 0.75 mmol), was added as a solid. The reaction mixture was stirred 2 h at room temperature, then overnight at 60° C. The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL). The desired product was extracted with three portions of ethyl acetate (3×10 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The crude product was purified by flash chromatography, using pure ethyl acetate as eluent. The desired product, e.g. N-(4-chlorophenyl)-4-{[2-(4-morpholinyl)ethyl]amino}benzenesulfonamide (184.2 mg, 62% yield) was obtained as a colorless oil, in 97% purity by BPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification. The reaction mixture was stirred 2 h at room temperature overnight at 60° C The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL) The desired product was extracted with three portions of ethyl acetate (3×10 mL) Combined organic phases were dried over magnesium sulfate before filtering removal of solvent The crude product was purified by flash chromatography

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

Procedure: 4-Chloroaniline (6.697 g, 52 mmol) was dissolved in pyridine (250 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.775 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (6.630 g, 58%), was obtained as a colorless solid, in 97.3% purity by HPLC (MaxPlot detection between 230 and 400 nm). Solvents were evaporated to dryness The crude oil was dissolved in ethyl acetate (150 mL) washed with 10% HCl (2×75 mL) and brine (1×75 mL) Organic phase was dried over magnesium sulfate before filtering removal of solvent The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1

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

Procedure: 4-Chloroaniline (6.697 g, 52 mmol) was dissolved in pyridine (250 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.775 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (6.630 g, 58%), was obtained as a colorless solid, in 97.3% purity by HPLC (MaxPlot detection between 230 and 400 nm). Solvents were evaporated to dryness The crude oil was dissolved in ethyl acetate (150 mL) washed with 10% HCl (2×75 mL) and brine (1×75 mL) Organic phase was dried over magnesium sulfate before filtering removal of solvent The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1

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

Procedure: To a suspention of NaH (100 mmol, 55-65% in oil) in dry dioxane (140 mL) was added 3-dimethylamino-1-propanol (11.90 mL, 100 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (9.53 g, 33.35 mmol, preparation described in example 66) in dry dioxane (35 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (75 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×100 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. N-(4-chlorophenyl)-4-[3-(dimethylamino)propoxy]benzenesulfonamide was obtained as a colorless oil, in 96% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification. The resulting mixture was heated 24 h at 100° C Solvents were evaporated NH4Cl saturated solution in water (75 mL) was added the desired product was extracted with three portions of ethyl acetate (3×100 mL) Combined organic phases were dried over magnesium sulfate before filtering removal of solvent

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2aminoethyl)morpholine (293 μL, 2.25 mmol) was dissolved in THF (7.5 mL) and was cooled down to −78° C. A 2.5N solution of nBuLi in hexane (1 mL, 2.5 mmol) was added dropwise. After 5 min. at −78° C., the mixture was stirred 1 h at −40° C. N-aryl-benzenesulfonamide building block XIII, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (214 mg, 0.75 mmol), was added as a solid. The reaction mixture was stirred 2 h at room temperature, then overnight at 60° C. The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL). The desired product was extracted with three portions of ethyl acetate (3×10 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The crude product was purified by flash chromatography, using pure ethyl acetate as eluent. The desired product, e.g. N-(4-chlorophenyl)-4-{[2-(4-morpholinyl)ethyl]amino}benzenesulfonamide (184.2 mg, 62% yield) was obtained as a colorless oil, in 97% purity by BPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification. The reaction mixture was stirred 2 h at room temperature overnight at 60° C The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL) The desired product was extracted with three portions of ethyl acetate (3×10 mL) Combined organic phases were dried over magnesium sulfate before filtering removal of solvent The crude product was purified by flash chromatography

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

Procedure: 4-Chloroaniline (6.697 g, 52 mmol) was dissolved in pyridine (250 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.775 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (6.630 g, 58%), was obtained as a colorless solid, in 97.3% purity by HPLC (MaxPlot detection between 230 and 400 nm). Solvents were evaporated to dryness The crude oil was dissolved in ethyl acetate (150 mL) washed with 10% HCl (2×75 mL) and brine (1×75 mL) Organic phase was dried over magnesium sulfate before filtering removal of solvent The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1