N-(2-aminoethyl)methanesulfonamide;hydrochloride

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

実験手順: N-[2-(Methylsulphonamido)ethyl]acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water (100 ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanol and ether gave the title compound as a white solid which was dried in vacuo at 60° C. (7.5 g, 42.9 mmol, 49%); δH [2H6]DMSO 8.22 (2H, br s), 7.42 (1H, t), 3.23 (2H, q), 2.87 (3H, s), 2.85-2.95 (2H, m). heated to reflux for a total of 3 hours After cooling the water was removed in vacuo the residue was left for several days at room temperature until crystallisation Trituration with a mixture of ethanol and ether

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

実験手順: N-[2-(Methylsulphonamido)ethyl]acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water (100 ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanol and ether gave the title compound as a white solid which was dried in vacuo at 60° C. (7.5 g, 42.9 mmol, 49%); δH [2H6]DMSO 8.22 (2H, br s), 7.42 (1H, t), 3.23 (2H, q), 2.87 (3H, s), 2.85-2.95 (2H, m). heated to reflux for a total of 3 hours After cooling the water was removed in vacuo the residue was left for several days at room temperature until crystallisation Trituration with a mixture of ethanol and ether

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

実験手順: N-[2-(Methylsulphonamido)ethyl]acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water (100 ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanol and ether gave the title compound as a white solid which was dried in vacuo at 60° C. (7.5 g, 42.9 mmol, 49%); δH [2H6]DMSO 8.22 (2H,br s), 7.42 (1H,t), 3.23 (2H,q), 2.87 (3H,s), 2.85-2.95 (2H,m). heated to reflux for a total of 3 hours After cooling the water was removed in vacuo the residue was left for several days at room temperature until crystallisation Trituration with a mixture of ethanol and ether

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 40 g (0.392 mol) of N-(2-aminoethyl)acetamide and 59.4 g (0.587 mol) of triethylamine were dissolved in 600 ml of dichloromethane. The solution was cooled down to 0 . . . +5° C. after which 67.2 g (0.587 mol) of methanesulfonyl chloride was added during a period of 1-1.5 h under continuous stirring, while keeping the temperature not higher than +5° C. during the addition. When the addition was finished the reaction mixture was stirred for another 3 hours while the temperature was allowed to rise to room temperature. After the reaction was completed the reaction mixture was evaporated to dryness. Dichloromethane saturated with ammonia (2000 ml) was added to the evaporation residue and the mixture was triturated for 15-30 min at room temperature. The formed precipitate was filtered off and the filtrate was evaporated to dryness. The evaporation residue was dissolved in 6 M hydrochloric acid (980 ml). The solution was heated to reflux (approx. 110° C.) and stirred at this temperature for 2 h. When the reaction was finished the reaction mixture was allowed to cool down to 60° C. and then evaporated to dryness under reduced pressure. The evaporation residue was dissolved in 460 ml of methanol and then again evaporated to dryness to remove traces of water. The residue was dissolved in another 460 ml of methanol after which 3 g of −activated carbon (Norit® SX1) was added. The mixture was stirred for 15 min at 30° C., and filtered. The methanol solution was concentrated to about one third of the original mass. The crystallization was initiated by adding 85 ml of dichloromethane during 1 h under constant stirring. The solution was seeded by adding approximately 200 mg of seeding material N-(2-aminoethyl)methanesulfonamide hydrochloride. The solution was stirred for 15 min after which slow dichloromethane addition (1600 ml) was continued over a period of 6 hours under constant stirring. The mixture was cooled to 5° C. and stirred at this temperature for another 3 hours. The crystals were filtered and washed with 2×70 ml of cold acetone. The product was dried under vacuum at 30° C. overnight. The yield was typically in the range of 70-80%. The solution was cooled down to 0 higher than +5° C. during the addition When the addition to rise to room temperature was evaporated to dryness Dichloromethane saturated with ammonia (2000 ml) was added to the evaporation residue the mixture was triturated for 15-30 min at room temperature The formed precipitate was filtered off the filtrate was evaporated to dryness The evaporation residue was dissolved in 6 M hydrochloric acid (980 ml) The solution was heated stirred at this temperature for 2 h to cool down to 60° C. evaporated to dryness under reduced pressure The evaporation residue was dissolved in 460 ml of methanol again evaporated to dryness to remove traces of water The residue was dissolved in another 460 ml of methanol after which 3 g of −activated carbon (Norit® SX1) was added The mixture was stirred for 15 min at 30° C. filtered The methanol solution was concentrated to about one third of the original mass The crystallization by adding 85 ml of dichloromethane during 1 h under constant stirring by adding approximately 200 mg of seeding material N-(2-aminoethyl)methanesulfonamide hydrochloride The solution was stirred for 15 min after which slow dichloromethane addition (1600 ml) was continued over a period of 6 hours under constant stirring The mixture was cooled to 5° C. stirred at this temperature for another 3 hours The crystals were filtered washed with 2×70 ml of cold acetone The product was dried under vacuum at 30° C. overnight

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At room temperature, 10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde, 6.5 g of compound N-(2-aminoethyl)methanesulfonamide hydrochloride, and 14.6 g of triethylamine in the mixture of dichloromethane/methanol (3:1) were stirred overnight, then cooled with ice-bath to 0° C., and 1.4 g of sodium borohydride was added at that temperature. The mixture was warmed to room temperature, stirred overnight, saturated sodium bicarbonate was added to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 5.7 g of the desired product, yield 45.0%. The mixture was warmed to room temperature stirred overnight to quench the reaction extracted with ethyl acetate The organic phase was washed with saturated sodium chloride solution dried over anhydrous sodium sulfate

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

実験手順: In a 500 ml reaction flask, tert-butyl 2-methylsulfonamidoethylaminoformate (25 g) and 350 ml of a mixture of ethanol and methanol were added. The mixture was stirred by an electromagnetic stirrer, fed with dry hydrogen chloride gas for 3 h, stirred at room temperature overnight, concentrated under a reduced pressure to a small volume, subjected to suction filtration to obtain 14.6 g of brown-gray powdery solid, yield 79.3%. were added stirred at room temperature overnight concentrated under a reduced pressure to a small volume subjected to suction filtration

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

実験手順: Methanesulphonyl chloride (16.8 g) in dry chloroform (25 ml) was added dropwise to a stirred solution of mono-N-acetylethylene diamine (15 g) and triethylamine (15 ml) in dry chloroform (25 ml) at 0°. The solution was stirred at ambient temperature for 60 hours. The reaction mixture was then extracted with water (3×50 ml) and the combined aqueous fractions were shaken with chloroform and separated. The aqueous fraction was evaporated in vacuo and the residue in methanol (100 ml) and concentrated hydrochloric acid (50 ml) was heated under reflux for 12 hours. The solvent was then evaporated in vacuo and the residue treated with methanol at reflux. The insoluble solid was filtered off and discarded. The filtrate was evaporated in vacuo and the residue treated with chloroform at reflux. The solvent was decanted leaving N-monomethanesulphonylethylene diamine, hydrochloride as a semi-solid also containing triethylamine hydrochloride. The product was used in the preparation of the product of Example 36 without further purification. The reaction mixture was then extracted with water (3×50 ml) the combined aqueous fractions were shaken with chloroform separated The aqueous fraction was evaporated in vacuo the residue in methanol (100 ml) and concentrated hydrochloric acid (50 ml) was heated under reflux for 12 hours The solvent was then evaporated in vacuo the residue treated with methanol at reflux The insoluble solid was filtered off The filtrate was evaporated in vacuo the residue treated with chloroform at reflux The solvent was decanted