3-(chloromethyl)-N-methylbenzamide

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

実験手順: 5 g (29.31 mmol) of 3-chloromethylbenzoic acid were suspended in 20 ml of abs. toluene, 5.23 g (43.96 mmol) of thionyl chloride were added dropwise and the mixture was stirred at 90° C. overnight. After cooling to RT, excess thionyl chloride and toluene were evaporated and the residue was dried under high vacuum for 1 h. Under argon, the residue was dissolved in 40 ml of abs. dichloromethane and cooled to 0° C., and 2.18 g (32.24 mmol) of methylamine hydrochloride were added. At 0° C., 7.58 g (58.62 mmol) of N,N-diisopropylethylamine were slowly added dropwise, and the reaction mixture was stirred at 0° C. for 15 min. 100 ml of dichloromethane were added, and the reaction mixture was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. After cooling to RT excess thionyl chloride and toluene were evaporated the residue was dried under high vacuum for 1 h Under argon, the residue was dissolved in 40 ml of abs dichloromethane and cooled to 0° C. the reaction mixture was stirred at 0° C. for 15 min the reaction mixture was washed three times with water The organic phase was dried over sodium sulfate filtered concentrated a rotary evaporator

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

実験手順: The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g). The mixture was poured to give an oily precipitate stirring continued for 1 hour The latter was filtered off washed with water, ethyl acetate and ether dried

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

実験手順: The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g). The mixture was poured to give an oily precipitate stirring continued for 1 hour The latter was filtered off washed with water, ethyl acetate and ether dried

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

実験手順: A solution of 3-chloromethylbenzoyl chloride (7.4 g, Aldrich) in DCM (35 ml) was added dropwise at 0° C. over 30 minutes to a stirred mixture of 30% aqu. methylamine (4.5 ml) and triethylamine (3.6 g) in DCM (50 ml). When addition was complete, the mixture was allowed to warm to room temperature over 1 hour with stirring. Further methylamine (0.5 ml) was added and the mixture stirred for a further 10 minutes, then washed with water, 1N aqu. HCl, 1N aqu. NaOH and brine, dried over MgSO4 and evaporated in vacuo to give the desired product as a colourless oil which solidified to a white solid on standing. When addition the mixture stirred for a further 10 minutes washed with water, 1N aqu NaOH and brine, dried over MgSO4 evaporated in vacuo

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

実験手順: To a suspension of 3-(chloromethyl)-N-methyl-benzamide (27.2 g, 148 mmol) in toluene (100 mL) was added thionyl chloride (16.2 mL, 222 mmol) at room temperature. The resulting suspension was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was azeotroped with toluene and dried under high vacuum. To a suspension of sodium azide (11.6 g, 178 mmol) in acetonitrile (140 mL) was added chlorotrimethylsilane (23.7 mL, 187 mmol) at room temperature and the suspension was stirred for 1.5 hours. The reaction mixture was cooled to −10° C. and the above crude imidoyl chloride (148 mmol) in acetonitrile (40 mL) was added over 5 minutes. The mixture was stirred for 2 hours at 0° C. and then stirred at room temperature for 15 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C. The resulting solution was stored in the refrigerator and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, 3-(1-methyltetrazol-5-yl)benzyl chloride was isolated as 24.5 g (79.5%) of a white amorphous solid, mp 63-65° C.; HRMS (ES+) cald. for C9H9ClN4 [(M+H)+] 209.0589, obsd. 209.0588. The resulting suspension was heated at reflux for 15 hours concentrated under vacuum The residue was azeotroped with toluene dried under high vacuum The reaction mixture was cooled to −10° C. The mixture was stirred for 2 hours at 0° C. stirred at room temperature for 15 hours extracted with ethyl acetate (2×100 mL) The combined organic extracts were washed with brine dried over anhydrous magnesium sulfate Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C the precipitated solids were collected by filtration washed with hexanes After drying in air

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

実験手順: To a solution of 3-(chloromethyl)-benzoic acid (34.1 g, 200 mmol) in toluene (125 mL) was added thionyl chloride (21.9 mL, 300 mmol) at room temperature. The resulting solution was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oily residue was azeotroped with toluene and dried under high vacuum to obtain the crude acid chloride. To a suspension of the above crude acid chloride (200 mmol) in dichloromethane (400 mL) was added methylamine hydrochloride (14.9 g, 220 mmol) at −5° C. to 0° C. Diisopropylethylamine (69.6 mL, 400 mmol) was added drop-wise over 15-20 minutes at 0° C. After completion of the addition, the mixture was stirred for 45 minutes at 0° C., then warmed to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with water (300 mL) and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave the crude solid which was dissolved in toluene at ˜60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and then washed with hexanes. After drying in air, 3-(chloromethyl)-N-methyl-benzamide (80%) was isolated as a light yellow solid. The resulting solution was heated at reflux for 15 hours concentrated under vacuum The resulting oily residue was azeotroped with toluene dried under high vacuum to obtain the crude acid chloride After completion of the addition warmed to room temperature After stirring at room temperature for 15 minutes the aqueous layer was extracted with dichloromethane (100 mL) The combined organic layers were washed with brine dried over anhydrous magnesium sulfate Filtration and concentration gave the crude solid which was stored in the refrigerator overnight the precipitated solids were collected by filtration washed with hexanes After drying in air

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

実験手順: 5 g (29.31 mmol) of 3-chloromethylbenzoic acid were suspended in 20 ml of abs. toluene, 5.23 g (43.96 mmol) of thionyl chloride were added dropwise and the mixture was stirred at 90° C. overnight. After cooling to RT, excess thionyl chloride and toluene were evaporated and the residue was dried under high vacuum for 1 h. Under argon, the residue was dissolved in 40 ml of abs. dichloromethane and cooled to 0° C., and 2.18 g (32.24 mmol) of methylamine hydrochloride were added. At 0° C., 7.58 g (58.62 mmol) of N,N-diisopropylethylamine were slowly added dropwise, and the reaction mixture was stirred at 0° C. for 15 min. 100 ml of dichloromethane were added, and the reaction mixture was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. After cooling to RT excess thionyl chloride and toluene were evaporated the residue was dried under high vacuum for 1 h Under argon, the residue was dissolved in 40 ml of abs dichloromethane and cooled to 0° C. the reaction mixture was stirred at 0° C. for 15 min the reaction mixture was washed three times with water The organic phase was dried over sodium sulfate filtered concentrated a rotary evaporator

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

実験手順: The product from step (a) (4.0 g), the product from step (b) (3.3 g) and anhy. K2CO3 (2.55 g) were taken up in DMF (25 ml) and stirred at room temperature for 60 hours. The mixture was poured with vigorous stirring into ice-water (175 ml) to give an oily precipitate. Ethyl acetate was added and stirring continued for 1 hour to solidify the precipitate. The latter was filtered off, washed with water, ethyl acetate and ether, and dried to give the desired product as a peach-coloured solid (4.5 g). The mixture was poured to give an oily precipitate stirring continued for 1 hour The latter was filtered off washed with water, ethyl acetate and ether dried

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

実験手順: A solution of 3-chloromethylbenzoyl chloride (7.4 g, Aldrich) in DCM (35 ml) was added dropwise at 0° C. over 30 minutes to a stirred mixture of 30% aqu. methylamine (4.5 ml) and triethylamine (3.6 g) in DCM (50 ml). When addition was complete, the mixture was allowed to warm to room temperature over 1 hour with stirring. Further methylamine (0.5 ml) was added and the mixture stirred for a further 10 minutes, then washed with water, 1N aqu. HCl, 1N aqu. NaOH and brine, dried over MgSO4 and evaporated in vacuo to give the desired product as a colourless oil which solidified to a white solid on standing. When addition the mixture stirred for a further 10 minutes washed with water, 1N aqu NaOH and brine, dried over MgSO4 evaporated in vacuo