Development of Efficient Manufacturing Method for Key Intermediate of Edoxaban

Abstract

Edoxaban is a Factor Xa inhibitor which has been approved and marketed all over the world as a new direct oral anticoagulant (DOAC). Traditional anticoagulants such as warfarin require monthly blood test, dietary controls and attention to the possibility of uncontrolled bleeding. DOACs have a more rapid onset, predictable effect, and few drug-drug interactions. Hence, they can be given in fixed doses without monitoring.

We have developed a novel highly efficient manufacturing method to access a key intermediate of edoxaban to increase the productivity and to reduce the manufacturing cost. A salient feature of the new synthetic route is a unique rearrangement reaction to construct a differentially protected 1,2-cis-diamine from 1,2-trans-aminoalcohol utilizing neighboring group participation with excellent stereo- and regioselectivity via sulfonyl aziridine intermediate by using of a Burgess-type reagent. In addition, a flow reaction system has also been applied to the process in large scale in order to suppress the degradation of the unstable reaction intermediate in the preparation of the reagent. Furthermore, the efficiency of the optical resolution of a chiral lactone intermediate was improved by employing enzymatic resolution instead of the diastereomeric salt crystallization. These three key technologies improved the overall yield and reduced the manufacturing cost.