Study On The Synthesis Of 2,3,4-trihydroxybenzoic Aldehyde

Levodopa and benserazide tablet (Madopar) is one of the most important drugs for Parkinson’s disease.2,3,4-trihydroxybenzoic aldehyde (PGA) is the key intermediate to synthesize benserazide hydrochloride, which is the components of Madopar. The research on this synthetic process has great value for industrial use.In this paper, in order to optimize the original process, the synthetic methods of PGA were reviewed and an improved route was designed according to the references. Using cheap cyclohexanone as the starting material,2,2,6,6-tetrachlorocyclohexanone was prepared by treating with chlorine and catalyzed by triphenyl phosphine hydrochloride in a yield of 91.8%, with a stable purity 99.5%. Then in the second step, under the catalysis of sodium citrate,2,2,6,6-tetrachlorocyclohexanone was hydrolyzed to pyrogallol. After extending the reaction time, the usage of citric acid was reduced to one quarter of conventional methods reported in the literature, while maintaining the yield 80.1% and purity (LC98.5%). Finally, in the third step, 2,3,4-trihydroxybenzoic aldehyde was synthesized by formylation of pyrogallol with triethyl orthoformate in the presence of anhydrous AICI3. The improvements and optimizations not only heightened the yield 20%, but simplified the extractant and solvent to the same. Using Ethyl acetate inside of dichloromethane, also matches the rule of single solvent usage to get higher recovery and lower cost.After our improvements, the synthesis process of PGA is more suitable for industrial production with a high overall yield, stable quality, short steps, easy operations and relatively low cost.