Ethyl 2-[5-(4-methylpiperazinyl)benzimidazol-2-yl]acetate

Synthesis

General procedure for the synthesis of ethyl 2-[5-(4-methylpiperazinyl)benzimidazol-2-yl]acetate from ethyl 3-ethoxy-3-iminopropionate and 5-(4-methylpiperazinyl)-2-nitroaniline: 43 mmol of 5-(4-methylpiperazin-1-yl)-2-nitroaniline (compound b) was dissolved in 150 mL of anhydrous ethanol, and then loaded after sufficient dissolution into the first raw material storage tank 1; in the second raw material storage tank 2, 20 mL of 3.6% by weight HCl was dissolved in 150 mL of anhydrous ethanol; 65 mmol of β-ethoxy-β-imino-propionic acid ethyl ester hydrochloride (Compound c) was dissolved in 150 mL of ethanol, and was loaded into the third raw material storage tank 3 after being fully dissolved. At this time, the molar ratio of 5-(4-methylpiperazin-1-yl)-2-nitroaniline to β-ethoxy-β-imino-propionic acid ethyl ester hydrochloride was 1:1.5. The solutions in the first raw material storage tank 1 and the second raw material storage tank 2 were simultaneously pumped into the reaction device, and passed through the first microstructured mixer 4 into the first microstructured reactor (Reactor 1) having an inner diameter of 0.5 mm and a volume of 50 mL Perform the reaction. The microreactor parameters were set: a continuous flow rate of 1.4 mL/min in the first step, a reaction temperature of 80°C, and a residence time of 8 min, and the reaction mainly produced the intermediate 4-(4-methylpiperazin-1-yl)isophthalamide. Subsequently, the solution in the third raw material storage tank 3 and the reaction solution obtained in the reactor 1 were simultaneously pumped into the second microstructure mixer 5, and entered into the second microstructure reactor (reactor 2) with an inner diameter of 0.5 mm and a volume of 50 ml to carry out the mixing reaction. The microreactor parameters were set: continuous flow rate of 3 mL/min for the second step, reaction temperature of 80°C, and residence time of 20 min. After completion of the reaction, the reaction solution was concentrated to obtain an oily substance, which was solubilized with 15 mL of water, extracted several times with CH2Cl2, the organic phases were combined, and the solvent was evaporated to obtain the orange-colored oily substance, i.e., compound d, with a yield of 91%.

References

[1] Patent: CN108610293, 2018, A. Location in patent: Paragraph 0032; 0039-0044; 0048; 0050; 0052; 0054; 0056