2-chloro-N-methylethanamine;hydrochloride

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

実験手順: 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. are added dropwise at 20° C under reflux for 5 hours extracted with 3 portions of 400 ml of chloroform the extract is washed with water dried over sodium sulphate concentrated on a rotary evaporator gives 56.8 g (51% of theory) of an oil

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

実験手順: 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. are added dropwise at 20° C under reflux for 5 hours extracted with 3 portions of 400 ml of chloroform the extract is washed with water dried over sodium sulphate concentrated on a rotary evaporator gives 56.8 g (51% of theory) of an oil

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

実験手順: 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 1 of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. are added dropwise at 20° C under reflux for 5 hours extracted with 3 portions of 400 ml of chloroform the extract is washed with water dried over sodium sulphate concentrated on a rotary evaporator gives 56.8 g (51% of theory) of an oil

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

実験手順: 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 1 of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. are added dropwise at 20° C under reflux for 5 hours extracted with 3 portions of 400 ml of chloroform the extract is washed with water dried over sodium sulphate concentrated on a rotary evaporator gives 56.8 g (51% of theory) of an oil

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

実験手順: A solution of 50 mg of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e, 9.3 mg of N-methyl-N-(2-chloroethyl)amine hydrochloride, 43 μL of diisopropylethylamine, and 35 mg of HATU in 1000 μL of DMF was stirred for 1 h. The mixture was diluted with 20 mL of water, and the resulting precipitate was collected by filtration. It was dissolved in dichloromethane and the solution was washed with water and dried (Na2SO4). The solvent was evaporated to give 42 mg of product. the resulting precipitate was collected by filtration It was dissolved in dichloromethane the solution was washed with water dried (Na2SO4) The solvent was evaporated

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

実験手順: A solution of 18 g of N-methyl-2-chloroethylamine hydrochloride, 20 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine and 40 ml of triethylamine in 150 ml of ethanol is heated under reflux for 2 hours. After evaporation, the residue is taken up in water, 0.1N sodium hydroxide is added and extraction is carried out with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue obtained is dissolved in an ethyl ether/acetone mixture and the solution is acidified by the addition of a solution of ethyl ether saturated with hydrogen chloride gas. The precipitate formed is filtered off, washed with ether and dried to give 12.6 g of 3-[2-(methylamino)ethylmercapto]-1,2,4-triazolo(4,3-a)pyridine hydrochloride in the form of crystals melting at 195°-7° C. under reflux for 2 hours After evaporation 0.1N sodium hydroxide is added extraction The chloroform phase is washed with water dried over sodium sulfate evaporated to dryness The residue obtained The precipitate formed is filtered off washed with ether dried

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After addition of further portions of cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) the mixture was heated at 70° C. for another 20 h. The reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound as formate salt. The salt was partitioned between ethyl acetate (15 ml) and 1 M aqueous sodium hydroxide solution (10 ml). The layers were separated. The aqueous layer was extracted with two 15 ml-portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (14 mg, 25%) as off-white solid. MS m/e: 455 ([M+H]+) was heated at 70° C. for another 20 h The reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml) The layers were separated The aqueous layer was extracted with two 5-ml portions of ethyl acetate The combined organic layers were concentrated in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After addition of further portions of cesium carbonate (246 mg, 0.754 mmol) and 2-methylaminoethyl chloride hydrochloride (65.4 mg, 0.503 mmol) the mixture was heated at 70° C. for another 20 h. The reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound as formate salt. The salt was partitioned between ethyl acetate (15 ml) and 1 M aqueous sodium hydroxide solution (10 ml). The layers were separated. The aqueous layer was extracted with two 15 ml-portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (14 mg, 25%) as off-white solid. MS m/e: 455 ([M+H]+) was heated at 70° C. for another 20 h The reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml) The layers were separated The aqueous layer was extracted with two 5-ml portions of ethyl acetate The combined organic layers were concentrated in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35.0 mg, 0.0803 mmol), cesium carbonate (105 mg, 0.321 mmol) and 2-methylaminoethyl chloride hydrochloride (41.8 mg, 0.321 mmol) in acetonitrile (0.8 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave title compound (19 mg, 48%) as off-white solid. MS m/e: 493 ([M+H]+) After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml) The layers were separated The aqueous layer was extracted with three 5-ml portions of ethyl acetate The combined organic layers were concentrated in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35.0 mg, 0.0803 mmol), cesium carbonate (105 mg, 0.321 mmol) and 2-methylaminoethyl chloride hydrochloride (41.8 mg, 0.321 mmol) in acetonitrile (0.8 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave title compound (19 mg, 48%) as off-white solid. MS m/e: 493 ([M+H]+) After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml) The layers were separated The aqueous layer was extracted with three 5-ml portions of ethyl acetate The combined organic layers were concentrated in vacuo

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

実験手順: 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. are added dropwise at 20° C under reflux for 5 hours extracted with 3 portions of 400 ml of chloroform the extract is washed with water dried over sodium sulphate concentrated on a rotary evaporator gives 56.8 g (51% of theory) of an oil

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

実験手順: Dissolve 3′-(4-fluoro-phenyl)-4-(1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.450 g, 1.33 mmol) in acetonitrile (3 mL) and add solid sodium hydroxide (0.186 g, 4.65 mmol). After 30 min. add (2-chloro-ethyl)-methyl-amine hydrochloride (0.190 g, 1.46 mmol) and tetrabutylammonium bisulfate (18 mg, 0.0531 mmol) then reflux the mixture for 20 hr. Cool and filter the mixture then evaporate. Purify using silica gel chromatography, eluting with 6:94 2N ammonia in methanol:DCM to give a yellow oil. Dissolve the solid in methanol and add ammonium chloride then sonicate the mixture for 10 min. Evaporate the solution to give the title compound as a white solid (0.139 g, 23%). MS (ES): m/z=396 [M+H]+. then reflux the mixture for 20 hr Cool filter the mixture then evaporate Purify eluting with 6:94 2N ammonia in methanol DCM to give a yellow oil then sonicate the mixture for 10 min Evaporate the solution