Large-Scale Synthesis of Herbicide Metabolites SYN545910 and M56

Abstract

Chemical herbicides are widely used to protect crops and are present in food and environmental media, such as agricultural lands and crops, posing a potential threat to environmental quality, food security, and human health. Certified reference materials (CRMs) for herbicide metabolite are necessary in food safety to ensure the accuracy, reliability, and traceability of analytical measurements for detecting and quantifying herbicide residues in food samples. A concise and large-scale synthesis of SYN545910 (1), a metabolite of herbicide bicyclopyrone (2), was developed over four steps, starting with commercially available building blocks, with an overall yield of 18.7%. The main feature of the synthesis is the formal [3+3] cycloaddition reaction, which constitutes the 2-alkyl-6-trifluoromethylnicotinic acid framework of SYN545910 (1) at the correct location for the substituent. A large-scale synthesis of M56 (3), a metabolite of herbicide tiafenacil (4), was developed over five steps, starting with commercially available building blocks, with an overall yield of 51.4%. The main feature of the synthesis is the condensation reaction, which constitutes the 6- trifluoromethyl-N-aryl uracil framework of M56 (3). All synthesis procedures are efficient and amenable to large-scale synthesis.