Synthesis and Characterization of Chiral Impurities of Edoxaban Tosylate Monohydrate, Used As an Anticoagulant Drug

Abstract

The present invention relates to identified and prepared chiral impurities in Edoxaban Tosylate monohydrate (1). This  work describes the synthesis of chiral impurities of each intermediate, including KSM and its drug substance and their characterization by spectral data (IR, MS,1H-NMR, and 13C-NMR). During the process development of Edoxaban Tosylate monohydrate (1) several unknown peaks were detected by high performance liquid column chromatography (HPLC) using chiral column. Edoxaban Tosylate monohydrate is the Tosylate salt form of edoxaban with binding one water molecule, an orally active inhibitor of coagulation factor Xa (activated factor X) with anticoagulant activity. Edoxaban having three chiral centers and has total of eight isomers, out of them only (SRS)-Edoxaban presents pharmacological activity being other seven are Edoxaban impurities. During the process development of edoxaban, the control of chiral impurities is challenging, and this is critical to remove from drug substance. Enantiomer of compound is led to form its starting material, and it tread on the heels of mechanism path up to final active pharmaceutical ingredients (API). This work helps to improve the efficacy and quality of the drug substance; therefore, concentration of these impurities must be controlled to the acceptable level.