Process Development For The Preparation Of Rupatadine

Rupatadine fumarate is an anti-allergic drug with dual action of antihistamine and platelet-activating factor(PAF)inhibition,which can suppress allergic reactions at different stages of allergic attack with high safety and efficacy.At present,there are two main synthetic processes for Rupatadine.We chose a route to synthesize rupatadine from ethyl nicotinate through Claisen condensation,hydrolytic decarboxylation,Huangminglong reduction reaction,oxidation reaction,Reissert-Henze reaction,Grignard reaction,intramolecular cyclization,Von Braun reaction,hydrolysis reaction,and N-alkylation reaction.The key steps in the synthetic route such as the oxidation reaction,Reissert-Henze reaction,and the cyclization reaction have been explored in detail.In the oxidation reaction,potential safety hazard are reduced by using methanol-water as a solvent and by dosing with hydrogen peroxide dropwise.The use of sodium tungstate as the catalyst for the oxidation reaction reduced the catalyst dosage,increased the yield and reduced the production cost.The structure of the by-products was determined by analyzing the factors influencing the Reissert-Henze reaction.The study showed a yield of 96.3% and a product to isomer ratio of 82.3:17.7 using acetonitrile as the solvent and dimethylcarbamoyl chloride as the chloroform reagent.Recrystallization in isopropanol gave a product of high purity with a recrystallization yield of 74.2%.It was shown that the cyclization reaction with Bronsted-Lewis conjugated superacid boronic anhydride/sulfuric acid in intramolecular cyclization reaction gave higher yields and less by-products.The structure of the by-products was determined by high-resolution mass spectrometry identification.The reaction was carried out by optimizing the ratio of sulfuric acid and boronic anhydride and using dropwise addition of sulfuric acid to suppress the formation of sulfonation by-products in 90.1%yield.The target compound rupatadine is produced from ethyl nicotinate as raw material by Claisen condensation reaction,hydrolytic decarboxylation,huangminglong reduction reaction,oxidation reaction,Reissert-Henze reaction,Grignard reaction,intramolecular cyclization,Von Braun reaction,hydrolysis reaction,N-alkylation reaction.The route was optimized with the steps of Reissert-Henze reaction and intramolecular cyclization reaction to reduce the formation of by-products,improve the yield and reduced potential production risks.The synthesis process route of rupatadine designed in this paper is characterized by safety and environmental protection,simple operation,high yield and green process,which is of great importance in industrialized large-scale production.