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5-(4-Methylpiperazin-1-yl)-2-nitroaniline (16 g, 67.8 mmol, 1.0 eq)Soluble in absolute ethanol (320mL),10% Pd/C (4.8 g) was added, charged with hydrogen, and stirred until the reaction was completed.3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (31.7 g, 162 mmol, 2.4 eq) was added under nitrogen, and the mixture was heated to 50 C for 3 hours.The reaction mixture was filtered, and the filtrate was evaporated evaporated.It is neutralized with ammonia, washed with water (2×100 mL), and the organic phase is concentrated.The crude product was purified by silica gel column chromatography (EtOAc)Obtained ethyl 2-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate as a white solid(3.23 g, yield: 15.7%).
With H2; sodium hydroxide;palladium-carbon; In hydrogenchloride;
Procedure A A 5000 mL, 4-neck flask was fitted with a stirrer, thermometer, condenser, and gas inlet/outlet. The equipped flask was charged with 265.7 g (1.12 mol. 1.0 eq) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2125 mL of 200 proof EtOH. The resulting solution was purged with N2 for 15 minutes. Next, 20.0 g of 5% Pd/C (50% H2O w/w) was added. The reaction was vigorously stirred at 40-50 C. (internal temperature) while H2 was bubbled through the mixture. The reaction was monitored hourly for the disappearance of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline by HPLC. The typical reaction time was 6 hours. After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50 C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2*250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2*400 mL) and dried at 50 C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
With H2; sodium hydroxide;palladium-carbon; In hydrogenchloride;
B. Synthesis of [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic Acid Ethyl Ester Procedure A A 5000 mL, 4-neck flask was fitted with a stirrer, thermometer, condenser, and gas inlet/outlet. The equipped flask was charged with 265.7 g (1.12 mol. 1.0 eq) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2125 mL of 200 proof EtOH. The resulting solution was purged with N2 for 15 minutes. Next, 20.0 g of 5% Pd/C (50% H2O w/w) was added. The reaction was vigorously stirred at 40-50 C. (internal temperature) while H2 was bubbled through the mixture. The reaction was monitored hourly for the disappearance of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline by HPLC. The typical reaction time was 6 hours. After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50 C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2*250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2*400 mL) and dried at 50 C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Taking 43 mmol 5 - (4 - methyl piperazinyl -1 - yl) -2 - nitroaniline (compound b) is dissolved in 150 ml of absolute ethanol, after fully dissolving loading in the 1st raw material storage tank 1 in; take 20 ml 3.6 wt % of HCl is dissolved in 150 ml of absolute ethanol, after fully dissolving loading in the 2nd raw material storage tank 2 in; taking 65 mmol β - ethoxy - β imino - propionic acid ethyl ester hydrochloride (compound c) is dissolved in 150 ml ethanol, after fully dissolving loading in the 3rd raw material storage tank 3 in, namely 5 - (4 - methyl piperazinyl -1 - yl) -2 - nitroaniline with β - ethoxy - β imine has short ethyl ester hydrochloride in a molar ratio of 1: 1.5, the 1st raw material storage tank 1 and the 2nd raw material storage tank 2 at the same time the pump enters micro channel of the feed liquid in the reaction device, by the 1st micro-structure mixer 4 enters into the coil internal diameter is 0.5 mm, the volume of 50 ml of the 1st micro-structured reactor (reactor 1) reaction, set up the micro-reactor parameter: 1st step of the continuous flow rate is 1.4 ml/min, the reaction temperature is 80 C, the dwell time of the 8 min, the reaction mainly producing the intermediate 4 - (4 - methyl piperazine -1 - yl) m-phenylenediamine; then the 3rd raw material storage tank 3 in the feed liquid and reactor 1 at the same time obtained effluent pumped into the 2nd micro-structure mixer 5 enters into the coil internal diameter is 0.5 mm, the volume of 50 ml of the 2nd micro-structured reactor (reactor 2) mixed in the reaction, set up the micro-reactor parameter: 2nd step of the continuous flow rate is 3 ml/min, the reaction temperature is 80 C, dwell time 20 min. Concentrating the reaction solution, obtaining oil object, for 15 ml water oily dissolving, for CH2Cl2A plurality of times of extraction, the combined organic phase, steaming and, be the oil of orange, to obtain compound d, and the yield is 91%,
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