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.

　供用後の盤ぶくれ現象の主な形態は，建設時に地山が比較的良好なためにインバートを設けなかった路盤が，掘削時の応力解放とその後の湧水等の影響を受け，強度低下することで路面等が隆起することである．本研究では，供用後にインバートを対策した事例から地山の劣化特性と対策工の現状を整理し，計測データから，対策が施されたトンネルのインバートの軸力を，建設段階で適用されている早期断面閉合の一次インバートの軸力と比較することにより，対策として設置するインバートとして必要な性能について考察する．そして盤ぶくれ現象を再現させた数値解析を用い，そのインバートの形状による支保の効果を比較し，合理的な構造を検討する．