Continuous-Flow Synthesis of an Important Liquid-Crystal Intermediate Using a Microreaction System

In this work, a microreaction system consisting of membrane-dispersion micromixers and microtube reactors was developed for the continuous synthesis of 4-(bromodifluoromethyl)-4′-cyclopentyl-3,5-difluorobiphenyl, an important intermediate of liquid-crystal compounds. Because of the high mass and heat transfer of the reaction, ortho-lithiation can be performed at −20 °C, which is much higher than the −70 °C required for the respective batch reaction. In addition, bromodifluoromethylation of aryllithium species can be achieved continuously with fewer byproducts. The yield of 4-(bromodifluoromethyl)-4′-cyclopentyl-3,5-difluorobiphenyl can reach 80.1% within 3 min. By contrast, in stirred tanks, the yield of 4-(bromodifluoromethyl)-4′-cyclopentyl-3,5-difluorobiphenyl only reaches 70.1% in 70 min and requires approximately 3 h at the industrial scale. The continuous-flow synthesis of 4-(bromodifluoromethyl)-4′-cyclopentyl-3,5-difluorobiphenyl in a microreaction system shows great potential for industrial appli...