Synthesis of 3-hydroxy-4-methoxy cinnamaldehyde as intermediate of advantame

3-Hydroxy-4-methoxy cinnamaldehyde is an important intermediate for the preparation of advantame, which is a novel dipeptide sweetener with super-high potency. At present, this intermediate is mainly synthesized by Aldol condensation reaction of isovanillin and acetaldehyde in the presence of strong base. However, since acetaldehyde is prone to self-condensation, there are problems such as harsh reaction conditions and low yield of 3-hydroxy-4-methoxy cinnamaldehyde. In this paper, a new process for preparation of 3-hydroxy-4-methoxy cinnamaldehyde by using vinyl acetate as a reactant in place of acetaldehyde to react with isovanillin was studied. The influences of reaction temperature, reaction time, NaOH dosage and molar ratio of isovanillin to vinyl acetate on the reaction were investigated by single factor experiments. On the basis of the single factor experiments, the response surface optimization was carried out. Results showed that the yield of 3-hydroxy-4-methoxy cinnamaldehyde was 71.44%±2.21% under optimal conditions: NaOH concentration of 4.5mol/L, reaction temperature of 10℃, reaction time of 12h and the molar ratio of isovanillin to vinyl acetate of 1∶2. In order to further improve the product yield, the strengthening effect of adding a phase transfer catalyst to the reaction system was explored. It was found that PEG-200 had a significant catalytic effect on the reaction, and the yield of 3-hydroxy-4-methoxy cinnamaldehyde achieved 83.12%±2.18%. © 2022 Chemical Industry Press. All rights reserved.