Study On The Synthesis And Impurity Of Rupatadine Fumarate

Rupatadine fumarate is a new-type antiallergic drug developed by Uriach pharmaceutical company in Spanish. Rupatadine fumarate is the unique drug in the market which has dual functions of anti-histamine and anti-platelet activating factor (PAF), and thus it possesses potential advantage over other allergy medcines with single pharmacological effect. The Rupatadine fumarate is expected to become the first-line drugs for the treatment of anaphylactia, and will have a huge market potential.A new synthetic route of rupatadine fumarate was established through incorporation of reported synthetic routes in literature. The 5-Methylnicotinic acid was employed as starting material, through esterification, reduction and chlorination to get intermediate 3-(Chloromethyl)-5-methyl-pyridine, followed by N-alkylation and salification, Rupatadine fumarate was furnished with total yield of 48.2%. After optimization of reaction conditions in every single step, a synthetic route suitable for industry production was achieved with available materials, simple synthetic process, easy to control, high purity and excellent yield. Meanwhile, the structure of rupatadine fumarate was confirmed by IR,1H NMR,13C NMR, MS.Due to the importance of impurity in drug development and production, the impurities of rupatadine fumarate was carefully examined. According to the synthetic route, we analysis the the possible impuritiesin Rupatadine fumarate.Then, the LC-MS analysis of raw Rupatadine fumarate, and the intermediates Desloratadine was performed to confirm the position of the intermediates. After that, the other unknown peaks in raw Rupatadine fumarate were analysed and two impurities were obtained by column chromatograph and directed-synthesis, with the structures were established by IR,1H NMR,13C NMR, MS and so on.At last, the possible mechanism to produce the two imputites were deduced and the reaction conditions were optimized to minimize them, which will be beneficial to production of high qulity Rupatadine fumarate in the future.