Efficient continuous synthesis of 2-[3-(trifluoromethyl)phenyl]malonic acid, a key intermediate of Triflumezopyrim, coupling with esterification-condensation-hydrolysis

Triflumezopyrim (TFM) is a novel mesoionic pyrido[1,2-α]pyrimidinones insecticide, which acts on nicotinic acetylcholine receptors (nAChRs) and has no cross-resistance with other insecticides. Herein, we firstly developed a new continuous flow approach to synthesis 2-[3-(trifluoromethyl)phenyl]malonic acid, a key intermate of TFM, coupling with esterification, condensation, and hydrolysis. All three-step reactions were optimized and transformed into a continuous synthesis mode by three micro reaction units. Compared with the batch mode, the total reaction time and overall separation yield were improved from more than 12 h and 60% to 18 min and 73.38%, respectively. The solvent consumption and waste emission were significantly reduced, which also provides an eco-friendly and efficient potential tool for the development and production of mesoionic pyrido[1,2-α]pyrimidinones insecticide. The continuous flow synthesis of 2-[3-(trifluoromethyl)phenyl]malonic acid was reported herein, which included esterification, condensation, and hydrolysis, three continuous flow units, and afforded a total conversion of 85.64%, an overall separation yield of 73.38%, and a total STY of 98 g L-1 h-1. [Display omitted]