Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers

详细信息    查看全文

• 作者：Makoto Michida ; Yoshihiro Takayanagi ; Makoto Imai ; Yukito Furuya ; Kenichi Kimura ; Takafumi Kitawaki ; Hiroshi Tomori ; Hisaki Kajino
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：November 15, 2013
• 年：2013
• 卷：17
• 期：11
• 页码：1430-1439
• 全文大小：501K
• 年卷期：v.17,no.11(November 15, 2013)
• ISSN：1520-586X

文摘

An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains three stereogenic centers. Especially, the chiral lactone is a key intermediate, and development of a scalable synthetic method was required, considering the quality, speed, and manufacturing cost. We established a scalable synthetic method of 1 from 4,6-O-benzylidene-d-glucose for early clinical studies. Furthermore, a highly efficient synthetic route of the chiral lactone for manufacturing was also successfully developed from n-butyryl chloride via Evans stereoselective alkylation, followed by stereoselective bromolactonization. In addition, a unique and highly efficient conversion protocol was developed from 伪-bromo-N-(2-nitrobenzenesulfonyl)amide to apparent rearranged diamine derivatives with a sequential aziridination鈥搒ubstitution reaction in one-pot.