2-chloro-N,N-diethylethanamine;hydrochloride

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

実験手順: 7.9 g tert-butyl 4-(4-hydroxyphenoxy)-piperidine-1-carboxylate (see WO2006/64218), 5.2 g (2-chloroethyl)-diethylamine hydrochloride and 16.6 g potassium carbonate are placed in 250 ml acetone. The reaction mixture is stirred at reflux temperature. After 4 hours the inorganic salts are suction filtered and the mixture is evaporated to dryness. The residue is combined with ethyl acetate. The organic phase is washed with a saturated NaHCO3 solution, dried and evaporated to dryness. 10.1 g of the product are obtained as an oil. at reflux temperature suction filtered the mixture is evaporated to dryness The organic phase is washed with a saturated NaHCO3 solution dried evaporated to dryness

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

実験手順: Combine 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (1 mmol) and sodium hydride (2 mmol) in tetrahydrofuran (10 mL). Add diethylaminoethylchloride hydrochloride (1 mmol). After 24 hours, partition the the reaction mixture between water and ethyl acetate. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo to give the title compound. partition the the reaction mixture between water and ethyl acetate Separate the organic layer dry over MgSO4 filter evaporate in vacuo

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After dissolving 114 mg of 1-(3-fluorophenyl)-3-{-4-[6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, there were added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylamine hydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, and the mixture was stirred at 50-60° C. for 16 hours. There were then added 17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassium bicarbonate and 1 ml of dimethylformamide, and the mixture was stirred overnight at the same temperature. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated saline, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 33 mg of a crude solid containing the title compound. This was washed with ethyl acetate to obtain 5 mg of the title compound. the mixture was stirred overnight at the same temperature was then returned to room temperature liquid separation and extraction The organic layer was washed with water and saturated saline concentrated to obtain 33 mg of a crude solid

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

実験手順: 4-Nitrophenoxy sodium dihydrate (29.39 g), 2-(diethylamino)ethylchloride hydrochloride (25.60 g), potassium carbonate (30.17 g) and water (60 ml) were added into xylene (100 ml) and the mixture was heat-refluxed for 2 hours while mixing and continuously removing water by azeotropic distillation. After reaction, insolubles were removed by filtration. Filtrate was added with ethyl acetate (100 ml) and extracted 3 times with 1N HCl (100 ml). Aqueous layer was adjusted to pH 10 with 1N sodium hydroxide and oily substance separated was extracted 3 times with ethyl acetate (100 ml). Ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated to obtain N,N-diethyl-2-(4-nitrophenoxy)ethylamine (28.19 g) as color-less oily substance. the mixture was heat-refluxed for 2 hours while mixing continuously removing water by azeotropic distillation After reaction, insolubles were removed by filtration Filtrate was added with ethyl acetate (100 ml) extracted 3 times with 1N HCl (100 ml) separated was extracted 3 times with ethyl acetate (100 ml) concentrated

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

実験手順: 4.9 g (60 mmol) of N-methylimidazole are added to 8.6 g (50 mmol) of 2-(diethylamino)ethyl chloride hydrochloride in 50 ml of absolute ethanol and the mixture is refluxed for 12 hours. the mixture is refluxed for 12 hours

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

実験手順: A solution of 5.2 g. of 2-diethylaminoethyl chloride hydrochloride in 35 ml. of dimethylsulfoxide is treated with 8.3 g. of finely ground dry potassium carbonate and stirred at room temperature for 15 minutes. Then, there are added thereto 3.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester; the mixture is stirred intensively for 18 hours under an atmosphere of nitrogen at room temperature and subsequently poured onto 80 ml. of ice-water. After the addition of 5 g. of sodium chloride, the separated oil is immediately extracted with ether, and the extract concentrated to about 30 ml. and treated with 30 ml. of 0.5-N hydrochloric acid. The mixture is thoroughly shaken and cooled in an ice-bath. The crystallized hydrochloride is isolated and purified in an analogous manner to that given in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 248°-250° C. (decomposition). Then, there are added subsequently poured onto 80 ml After the addition of 5 g of sodium chloride, the separated oil is immediately extracted with ether the extract concentrated to about 30 ml and treated with 30 ml The mixture is thoroughly shaken cooled in an ice-bath

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

実験手順: According to the procedure described in Example 1, 28.5 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid methylamide are treated with 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is heated at 70° C. for 5 hours, then cooled and poured into 4 liters of ice-water. After the addition of 200 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is digested with ether, removed by filtration and washed with ether, and there is obtained a first portion of crude 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide having a melting point of 187°-190° C. The ethereal filtrate is extracted with 1-N sulfuric acid and the acidic extract is made alkaline at 0°-5° C. with concentrated ammonia solution. Then, the separated oil is extracted with methylene chloride and the solution dried over sodium sulfate. After evaporation, there is obtained an oil which crystallizes from ether, and is obtained as a second portion of reaction product; melting point 187°-190° C. Both portions of the reaction product are recrystallized together from ethanol, and 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide is obtained in the form of colorless needles having a melting point of 190°-192° C. cooled After the addition of 200 g of sodium chloride, the separated product is extracted with methylene chloride The organic phase is washed with a saturated solution of sodium chloride dried over sodium sulfate concentrated to dryness under reduced pressure removed by filtration washed with ether there is obtained a first portion of crude 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid methylamide having a melting point of 187°-190° C The ethereal filtrate is extracted with 1-N sulfuric acid the acidic extract at 0°-5° C. Then, the separated oil is extracted with methylene chloride the solution dried over sodium sulfate After evaporation there is obtained an oil which crystallizes from ether is obtained as a second portion of reaction product Both portions of the reaction product are recrystallized together from ethanol

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

実験手順: A solution of 27.2 g. of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester in 480 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.33 mol. of sodium hydride (14.4 g. of a 5 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. To this mixture, there are added at -10° C. to -5° C. 27.2 g. of 2-diethylaminoethyl chloride hydrochloride; the mixture is then stirred at room temperature for 1 hour and subsequently heated for 3 hours at 60° C. After cooling, the mixture is poured into 4 liters of ice-water with stirring; 200 g. of sodium chloride are added and the oily precipitate is separated by decantation. The latter is immediately dissolved in methylene chloride and the organic solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 100 ml. of ether and filtered; the filtrate is treated with 180 ml. of 0.5-N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is removed by filtration, washed with water and ether and then dissolved in 200 ml. of methylene chloride. After separation of the aqueous layer, the methylene chloride solution is dried over sodium sulfate, filtered and treated portionwise with 150 ml. of ether, whereby there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition). To this mixture, there are added at -10° C. to -5° C subsequently heated for 3 hours at 60° C After cooling with stirring the oily precipitate is separated by decantation The latter is immediately dissolved in methylene chloride is washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate concentrated to dryness The resulting oil is dissolved in 100 ml of ether and filtered the filtrate is treated with 180 ml of 0.5-N hydrochloric acid and thoroughly shaken After cooling in an ice-bath the crystallized hydrochloride is removed by filtration washed with water and ether dissolved in 200 ml After separation of the aqueous layer the methylene chloride solution is dried over sodium sulfate filtered treated portionwise with 150 ml

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 26.5 g. of 3-phenylisoindole-1-carboxylic acid ethyl ester in 600 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.40 mol. of sodium hydride (17.5 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. Then, at -10° C. to -5° C. there are added 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is stirred for 1 hour at room temperature and subsequently heated for 3 hours at 60° C. The mixture is cooled and poured into 8 liters of ice-water. After the addition of 300 g. of sodium chloride, the oily precipitate is separated by decantation and immediately dissolved in methylene chloride. The solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 200 ml. of ether, treated with 280 ml. of 0.5 -N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the separated hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in methylene chloride. The aqueous layer is separated and the methylene chloride solution is dried over sodium sulfate and filtered. After the addition of ether, there is obtained 2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 230°-232° C. (decomposition). Then, at -10° C. to -5° C. there are added 34.5 g The mixture is stirred for 1 hour at room temperature The mixture is cooled After the addition of 300 g of sodium chloride, the oily precipitate is separated by decantation immediately dissolved in methylene chloride is washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate concentrated to dryness The resulting oil is dissolved in 200 ml of ether, treated with 280 ml of 0.5 -N hydrochloric acid and thoroughly shaken After cooling in an ice-bath the separated hydrochloride is removed by filtration under suction washed with water and ether dissolved in methylene chloride The aqueous layer is separated the methylene chloride solution is dried over sodium sulfate filtered After the addition of ether

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

実験手順: Meanwhile, in a second flask, 4.6 g. of sodium are dissolved in 100 ml. of ethanol and treated at 0° C. with 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. After dilution with 50 ml. of dimethylformamide and stirring for 30-40 minutes in an ice-bath, the obtained fine suspension is added dropwise at 0°-2° C. over a period of 15-20 minutes to the sodium derivative of 5-chloro-3-phenyl-isoindole-1-carboxylic acid ethyl ester prepared as in the foregoing paragraph. The mixture is subsequently stirred for 30 minutes at room temperature and then heated at 60° C. for 3 hours. After cooling, the mixture is poured into 4 liters of ice-water, 200 g. of sodium chloride are added and the separated oily product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is then taken up in 200 ml. of ether, treated with 280 ml. of 0.5-N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in 700 ml. of methylene chloride. The aqueous layer is separated; the organic phase is dried over sodium sulfate, filtered and treated portionwise with 450 ml. of ether, whereby there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride in the form of colorless crystals having a melting point of 248°-250° C. (decomposition). Crystallization from methylene chloride/ether does not increase the melting point. heated at 60° C. for 3 hours After cooling the separated oily product is immediately extracted with methylene chloride is washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate concentrated to dryness of ether, treated with 280 ml of 0.5-N hydrochloric acid and thoroughly shaken After cooling in an ice-bath the crystallized hydrochloride is removed by filtration under suction washed with water and ether dissolved in 700 ml The aqueous layer is separated the organic phase is dried over sodium sulfate filtered treated portionwise with 450 ml

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

実験手順: The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 259 mg of 2-diethylaminoethylchloride hydrochloride were used. As a result, 254 mg of 3-(2-diethylaminoethyl)-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained. The reaction procedure of Example 11

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

実験手順: The reaction procedure of Example 11 was followed except that 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 54 mg of lithium hydride and 633 mg of 2-diethylaminoethylchloride hydrochloride were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform-3% methanol). The resulting compound was then recrystallized from a mixture of ether and hexane containing 4 N hydrogen hydride in dioxane to obtain 556 mg of 3-(2-diethylaminoethyl)-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one monohydrochloride. The reaction procedure of Example 11 The resulting residue was then purified through silica gel column chromatography (eluant: chloroform-3% methanol) The resulting compound was then recrystallized from a mixture of ether and hexane containing 4 N hydrogen hydride in dioxane