6-(trifluoromethyl)pyrid-2-one: Development and scale-up of a ring synthesis route based on trifluoroacetic anhydride

Three routes to 6-(trifluoromethyl)pyrid-2-one involving de novo synthesis of the pyridine ring have been investigated which would potentially allow rapid semi-technical scale manufacture, A route starting from ethyl 4,4,4-trifluoroacetoacetate (beta-keto ester route) has been demonstrated, Development of the route was attempted; however, poor yields at a number of stages and scale-up difficulties made this route unattractive for commercial use, A four-stage route starting from trifluoroacetic anhydride and an alkyl vinyl ether (TFAA route) has been developed which gives good yields and productivity for all stages, The final stage of this route is a difficult decarboxylation of a nicotinic acid derivative, but an 80% yield of the required pyridone with a purity of > 99.5% could be achieved without a separate purification stage, The route was scaled up to 2000 L, and several hundred kilograms of product was prepared.