2-(dimethylamino)ethanethiol;hydrochloride

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

実験手順: The oil prepared in Step 10 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromotography on silica gel, eluting with 20:1 CH2Cl2 : MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O:C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98. The solvent was removed on a rotary evaporator the residue was purified by flash chromotography on silica gel eluting with 20:1 CH2Cl2

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

実験手順: The title compound of Step 10 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromotography on silica gel, eluting with 20:1 CH2Cl2 :MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98. The solvent was removed on a rotary evaporator the residue was purified by flash chromotography on silica gel eluting with 20:1 CH2Cl2

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 200 ml of acetonitrile was added to 28.3 g of 2-dimethylaminoethanethiol hydrochloride, and after 80 ml of sodium methoxide-containing 28% methyl alcohol solution was added thereto with cooling in an ice bath, 32.9 g of ethyl 4-chloroacetoacetate was dropwise added thereto with cooling in an ice bath. After the dropwise addition, the whole was stirred for 2 hours at 40° C., and then the inorganic salt was separated by filtration and the resulting filtrate was dried under reduced pressure. The oily substance obtained was purified by silica gel column chromatography (with moving phase solvent of chloroform/methyl alcohol, 10/1) to obtain 41.8 g of ethyl 4-(2-dimethylaminoethylthio)acetoacetate. To 23.3 g of the ethyl 4-(2-dimethylaminoethylthio)acetoacetate thus-obtained were added 8.4 g of 3-amino-1,2,4-triazole and 4.0 ml of acetic acid, and the whole was heated under reflux for 4 hours. After the reaction, 100 ml of methyl alcohol was added to the reaction solution and stirred with cooling in an ice bath, and the crystal precipitate was taken out by filtration and recrystallized from 300 ml of methyl alcohol to obtain 10.2 g of the desired product. M.P.: 109°-110° C. was added with cooling in an ice bath with cooling in an ice bath After the dropwise addition the inorganic salt was separated by filtration the resulting filtrate was dried under reduced pressure The oily substance obtained was purified by silica gel column chromatography (with moving phase solvent of chloroform/methyl alcohol, 10/1)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5.0 g of 10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacial acetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride. After the addition is complete, the mixture is heated to 90° C. whereupon it becomes homogenous. The solution is cooled to 25° C. and 15.4 ml of boron trifluoride etherate is added. After stirring for 3 days at 25° C., an additional 8 ml of boron trifluoride etherate is added and the solution is heated at 60° C. for 5 hours. The reaction mixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C. The mixture is extracted with ether and the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution provides 2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which is converted to its hydrochloride, mp 209°-211° C. After the addition The solution is cooled to 25° C. the solution is heated at 60° C. for 5 hours The mixture is extracted with ether the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° C., poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid. extracted into ethyl acetate The ethyl acetate solution is dried over anhydrous potassium carbonate concentrated under reduced pressure to give an oil The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid

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

実験手順: To a stirred solution of 2-dimethylaminoethanethiol hydrochloride (14.17 g, 0.10 mol) in 125 ml of dry DMF was added portionwise 60% sodium hydride in mineral oil (8.0 g, 0.2 mol) under a nitrogen atmosphere over 1/2 hour with warming on the steam bath. The mixture was stirred an additional 1/2 hour and then cooled in ice. To the cold suspension was added dropwise a solution of 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (7.66 g, 0.025 mol) in 25 ml of DMF. The mixture was stirred for an additional 1 hour at ice bath temperature. The mixture was filtered and the filtrate was concentrated in vacuo at 0.5 mm at room temperature. The solid residue was combined with the filtered solid and was dissolved in 3N HCl (100 ml). The acid solution was extracted with CHCl3 (2×50 ml), neutralized with NaHCO3 and concentrated to dryness in vacuo. The residual solid was extracted with CHCl3 (3×100 ml). The CHCl3 extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. The solid obtained contained some polar impurity which was removed by trituration with hot water. There was recovered 2.8 g of product (Yield 34%); m.p. 132-133%. with warming on the steam bath cooled in ice The mixture was stirred for an additional 1 hour at ice bath temperature The mixture was filtered the filtrate was concentrated in vacuo at 0.5 mm at room temperature was dissolved in 3N HCl (100 ml) The acid solution was extracted with CHCl3 (2×50 ml) concentrated to dryness in vacuo The residual solid was extracted with CHCl3 (3×100 ml) The CHCl3 extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo at room temperature The solid obtained was removed by trituration with hot water

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5.0 g of 10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacial acetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride. After the addition is complete, the mixture is heated to 90° C. whereupon it becomes homogeneous. The solution is cooled to 25° C. and 15.4 ml of boron trifluoride etherate is added. After stirring for 3 days at 25° C., an additional 8 ml of boron trifluoride etherate is added and the solution is heated at 60° C. for 5 hours. The reaction mixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C. The mixture is extracted with ether and the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution provides 2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which is converted to its hydrochloride, mp 209°-211° C. After the addition The solution is cooled to 25° C. the solution is heated at 60° C. for 5 hours The mixture is extracted with ether the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution

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

実験手順: 500 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(bromomethyl)benzoic acid via Procedure E. 170 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 2-(dimethylamino)ethanethiol hydrochloride via Procedure Q. 140 mg of crude N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylthio)methyl)benzamide was reacted with oxone via Procedure R. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylsulfonyl)methyl)benzamide. MS (Q1) 458.3 (M)+. The crude product was purified by reverse phase HPLC

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

実験手順: 500 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(bromomethyl)benzoic acid via Procedure E. 170 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 2-(dimethylamino)ethanethiol hydrochloride via Procedure Q. 140 mg of crude N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylthio)methyl)benzamide was reacted with oxone via Procedure R. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylsulfonyl)methyl)benzamide. MS (Q1) 458.3 (M)+. The crude product was purified by reverse phase HPLC

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5.0 g of 10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacial acetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride. After the addition is complete, the mixture is heated to 90° C. whereuponit becomes homogenous. The solution is cooled to 25° C. and 15.4 ml of boron trifluoride etherate is added. After stirring for 3 days at 25° C., an additional 8 ml of boron trifluoride etherate is added and the solution is heated at 60° C. for 5 hours. The reaction mixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C. The mixture is extracted with ether and the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution provides 2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which is converted to its hydrochloride, mp 209°-211° C. After the addition The solution is cooled to 25° C. the solution is heated at 60° C. for 5 hours The mixture is extracted with ether the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5.0 g of 10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacial acetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride. After the addition is complete, the mixture is heated to 90° C. whereupon it becomes homogenous. The solution is cooled to 25° C. and 15.4 ml of boron trifluoride etherate is added. After stirring for 3 days at 25° C., an additional 8 ml of boron trifluoride etherate is added and the solution is heated at 60° C. for 5 hours. The reaction mixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C. The mixture is extracted with ether and the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution provides 2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which is converted to its hydrochloride, mp 209°-211° C. After the addition The solution is cooled to 25° C. the solution is heated at 60° C. for 5 hours The mixture is extracted with ether the combined extracts are washed with 20% sodium hydroxide solution, water, saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered Chromatography of the filtrate on silica gel with 5% methanol/dichloromethane elution

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

実験手順: 2-Dimethylaminoethanethiol hydrochloride salt (1.46 g, 10.0 mmol) and sodium hydride (60% in oil, 0.88 g, 22.0 mmol) were added to THF (50 ml), and 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol) was added thereto. The mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.00 g, 48%) as pale yellow crystals. was added The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated the residue was recrystallized from n-hexane-ethyl acetate