N-(2-aminoethyl)methanesulfonamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Prepared by the method of example 2 step a), using the product of example 4, step b) and N-[2-aminoethyl]-methanesulfonamide, Prepared by the method of example 2 step a),

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

Procedure: Prepared by the method of example 2 step a), using the product of example 4, step b) and N-[2-aminoethyl]-methanesulfonamide, Prepared by the method of example 2 step a),

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

Procedure: 30 g (2.1×10-1 mols) of 2-methanesulfonylaminoethylamine and 18.1 g (2.3×10-1 mols) of carbon bisulfide were dispersed into 10 ml of ethyl acetate. 32.8 g (2.3×10-1 mols) of triethylamine was added dropwise to the dispersion while stirring at room temperature. The admixture was allowed to react for about 4 hours while the internal temperature thereof was maintained at 40° C. 70 ml of ethanol was added to the reaction system. The resulting crystal was filtered off and then washed with 30 ml of ethanol to obtain 54.0 g of triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate as an intermediate product. 54.0 g (1.7×10-1 mols) of the thus-obtained triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate was dispersed into 75 ml of ethanol. The dispersion was stirred while the internal temperature thereof was maintained at 7° to 8° C. under ice cooling. 28.6 g (1.7×10-1 mols) of ethyl bromoacetate was added dropwise to the dispersion. The dispersion was stirred for about 1 hour while the internal temperature was maintained at 20° C. by suppressing heat generation under ice cooling. The dispersion was further stirred for about 1 hour at room temperature. The resulting reaction product was put into 300 ml of water. The aqueous mixture was extracted with 500 ml of ethyl acetate. The mixture was then washed with water. The resulting ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate solution was filtered, and the filtrate was concentrated to obtain 43.7 g of 3-(2-methanesulfonylaminoethyl)rhodanine (yield: 100%). to react for about 4 hours while the internal temperature thereof was maintained at 40° C The resulting crystal was filtered off washed with 30 ml of ethanol

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

Procedure: 30 g (2.1×10-1 mols) of 2-methanesulfonylaminoethylamine and 18.1 g (2.3×10-1 mols) of carbon bisulfide were dispersed into 10 ml of ethyl acetate. 32.8 g (2.3×10-1 mols) of triethylamine was added dropwise to the dispersion while stirring at room temperature. The admixture was allowed to react for about 4 hours while the internal temperature thereof was maintained at 40° C. 70 ml of ethanol was added to the reaction system. The resulting crystal was filtered off and then washed with 30 ml of ethanol to obtain 54.0 g of triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate as an intermediate product. 54.0 g (1.7×10-1 mols) of the thus-obtained triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate was dispersed into 75 ml of ethanol. The dispersion was stirred while the internal temperature thereof was maintained at 7° to 8° C. under ice cooling. 28.6 g (1.7×10-1 mols) of ethyl bromoacetate was added dropwise to the dispersion. The dispersion was stirred for about 1 hour while the internal temperature was maintained at 20° C. by suppressing heat generation under ice cooling. The dispersion was further stirred for about 1 hour at room temperature. The resulting reaction product was put into 300 ml of water. The aqueous mixture was extracted with 500 ml of ethyl acetate. The mixture was then washed with water. The resulting ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate solution was filtered, and the filtrate was concentrated to obtain 43.7 g of 3-(2-methanesulfonylaminoethyl)rhodanine (yield: 100%). to react for about 4 hours while the internal temperature thereof was maintained at 40° C The resulting crystal was filtered off washed with 30 ml of ethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-(methanesulphonamido)ethylamine (0.350 g, 2.53 mmol). On completion of the reaction the mixture was acidified with dilute HCl and diluted with water, but no solid was formed. The mixture was concentrated in vacuo, and the residue was washed with acetone, 2N HCl and acetone again, and dried at 60° C. in vacuo to give the title compound as a yellow solid (0.210 g, 0.340 mmol, 78%); δH [2H6]DMSO 12.01 (1H, s), 9.82 (1H, br s), 9.77 (1H, s), 8.88 (1H, s), 8.40 (1H, d), 8.02 (1H, d), 7.76 (2H, d), 7.31-7.53 (6H, m), 7.14 (2H, d), 6.84 (1H, d), 5.18 (2H, s), 4.40 (2H, s), 3.34-3.48 (2H, m), 3.08-3.18 (2H, m), 2.96 (3H, s); m/z (M+1+) 544. On completion of the reaction the mixture no solid was formed The mixture was concentrated in vacuo the residue was washed with acetone, 2N HCl and acetone again dried at 60° C. in vacuo

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

Procedure: In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-(methanesulphonamido)ethylamine (0.350 g, 2.53 mmol). On completion of the reaction the mixture was acidified with dilute HCl and diluted with water, but no solid was formed. The mixture was concentrated in vacuo, and the residue was washed with acetone, 2N HCl and acetone again, and dried at 60° C. in vacuo to give the title compound as a yellow solid (0.210 g, 0.340 mmol, 78%); δH [2H6]DMSO 12.01 (1H, s), 9.82 (1H, br s), 9.77 (1H, s), 8.88 (1H, s), 8.40 (1H, d), 8.02 (1H, d), 7.76 (2H, d), 7.31-7.53 (6H, m), 7.14 (2H, d), 6.84 (1H, d), 5.18 (2H, s), 4.40 (2H, s), 3.34-3.48 (2H, m), 3.08-3.18 (2H, m), 2.96 (3H, s); m/z (M+1+) 544. On completion of the reaction the mixture no solid was formed The mixture was concentrated in vacuo the residue was washed with acetone, 2N HCl and acetone again dried at 60° C. in vacuo

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

Procedure: 5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), N-(2-aminoethyl)methylsulphonamide (12.9 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (481 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-[6-methyl-4′-({[2-(methylsulphonylamino)ethyl]amino}carbonyl)-1,1′-biphenyl-3-yl]-3-furamide (37 mg, 90%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.59,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.45,(2H, d), 7.27,(1H, d), 7.17,(1H, t), 6.98,(1H, m), 3.40,(2H, q), 3.13,(2H, q), 2.91,(3H, s), 2.19,(3H, s). LCMS: retention time 2.82 min, MH+442. washed with water (2×30ml) dried (magnesium sulphate) The solvent was evaporated under vacuum the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2)

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

Procedure: In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-(methanesulphonamido)ethylamine (0.350 g, 2.53 mmol). On completion of the reaction the mixture was acidified with dilute HCl and diluted with water, but no solid was formed. The mixture was concentrated in vacuo, and the residue was washed with acetone, 2N HCl and acetone again, and dried at 60° C. in vacuo to give the title compound as a yellow solid (0.210 g, 0.340 mmol, 78%); δH [2H6]DMSO 12.01 (1H,s), 9.82 (1H, br s), 9.77 (1H,s), 8.88 (1H,s), 8.40 (1H,d), 8.02 (1H,d), 7.76 (2H,d), 7.31-7.53 (6H,m), 7.14 (2H,d), 6.84 (1H,d), 5.18 (2H,s), 4.40 (2H,s), 3.34-3.48 (2H, m), 3.08-3.18 (2H,m), 2.96 (3H,s); m/z (M+1+) 544. On completion of the reaction the mixture no solid was formed The mixture was concentrated in vacuo the residue was washed with acetone, 2N HCl and acetone again dried at 60° C. in vacuo