Synthesis of 2-methoxy-5-methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitrile. A sequential application of experimental designs

An application of 2^4-1 fractorial factorial design for optimizing the yield of the synthesis of 2-methoxy-5-methyl-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitrile (4a) obtained from methyl methacrylate (3a) and malonodinitrile is described. A set of 16 statistically designed experiments analyzing the influence of five factors (order of addition of the reagents, amount and way of preparation of the sodium methoxide. reaction lime and influence of light) and its interactions upon yield was performed. The amount and nature of the sodium methoxide combined with the reaction time were found to have a significant influence upon the response. Thus, the yield was 54% when the reaction was carried out by adding the methyl methacrylate first, with a 1.5:1 molar ratio of sodium methoxide: 3a (the NaOMe being generated in situ), a reaction time of 30 min and unprotected against light.