Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

Abstract

We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process.

Stereoinvertive Deoxyamination of trans-2-Aminocyclohexanol Using Bose–Mitsunobu Azidation and Staudinger Reaction for the Stereoselective Synthesis of Edoxaban

“…All manipulations of air-and/or moisture-sensitive compounds were performed using standard Schlenk techniques. 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra were obtained from measurements at ambient temperature on a JEOL 500SS spectrometer (JNM-ECA500). Chloroform−d 1 (CDCl 3 ) containing 0.03% tetramethylsilane (TMS) (99.8% D, KANTO Chemical Co., Inc.) was used as a solvent for NMR measurements at room temperature.…”

“…Daiichi-Sankyo’s original synthetic route is shown in Scheme . Bromolactone 1 , readily derived from ( S )-3-cyclohexene-1-carboxylic acid, was converted into bromoalcohol 2 by the ring-opening aminolysis of the lactone with dimethylamine.…”

“…Subsequently, process chemists at Daiichi-Sankyo Co., Ltd. have also reported an improved method for the synthesis of the central skeleton 8·(CO 2 H) 2 by utilizing tethers to conduct stereospecific intramolecular reactions (Scheme ). The aminoalcohol 4 was synthesized from bromolactone 1 , similar to Scheme , and for the resulting aqueous solution of 4 , a Burgess-type reagent was used for sulfonylation to produce 13 . A mesyl group was introduced on the hydroxy group of 13 to afford 14 .…”

“…However, from a safety viewpoint, this process should be performed at the lowest possible temperature. In addition, regarding the diastereoselectivity, it was reported that the S N 2 reaction under heating conditions produced more than 10% of undesired diastereomers under all reaction conditions, which is due to the strong influence of neighboring group participation under heating conditions …”

Asymmetric Synthesis of Optically Active 3-Cyclohexene-1-carboxylic Acid Utilizing Lactic Ester as a Chiral Auxiliary in the Diastereoselective Diels–Alder Reaction

“…The optically active 3-cyclohexene-1-carboxylic acid ( 1 ) is one of the most important chiral building blocks frequently found in an array of active pharmaceutical ingredients (APIs) (Figure ). For example, it is an important starting material of edoxaban, FK-506, BMS-978589, oseltamivir, and other pharmaceuticals . In the syntheses of these APIs, the olefin moiety of 1 was stereoselectively functionalized by making use of the stereochemistry of the carboxy group in 1 to construct contiguous stereogenic centers.…”