The Synthesis Of Edoxaban And Its Related Substances

Edoxaban is a selective direct inhibitor of FXa which was developed by Daiichi Sankyo Company Limited. It can be used to suppress venous thromboembolism of the patients who have the surgery with their lower limbs. Edoxaban went on sale in Japan in July,2004. The market prospect is very broad.This article contains two parts:First is the synthesis process of Edoxaban; the second is the synthesis of related substances of Edoxaban.After a lot of literature research and experimental studies, we identified a suitable industrial synthetic route of Edoxaban. Edoxaban consists of three main intermediates. The (S)-3-cyclohexen-1-carboxylic acid is the starting material, After the addition of iodine, esterification, nucleophilic substitution reaction, palladium carbon reduction, amino protection, Walden inversion reaction, ester and amide bond hydrolysis reaction, we get the (1R,2S,5S)-2-azido-5-[(dimethylamino) carbonyl]-cyclohexyl carbamate. Eventually, after 17-step reactions, we get the final product Edoxaban. The route is suitable for industrial production because it has a shorter reaction period, lower raw material prices, higher product yields. After the Optimization of related technology, the total yield was raised to 1.69% from 0.88%.We not only analyzed and identified the related substances during the reaction, but also designed the synthetic routes of related substances. Eventually, we got 11 related substances.