Practical synthesis of ER-40133, a novel dual inhibitor of NEP and ACE

ORGN 813

Akio Kayano, a-kayano@hhc.eisai.co.jp1, Makoto Kotake2, Kozo Akasaka3, Hiroshi Akamatsu4, Yuki Komatsu1, Naoyuki Shimomura1, Toshikazu Shimizu5, Katsuya Tagami1, Hiroyuki Naka1, Kenji Hayashi6, Yuichi Kimoto5, Tomohiro Matsushima7, Naoki Yoneda2, Shinji Suda6, Yoshiharu Daiku8, Mamoru Saito9, Toshiyuki Matsuoka9, and Shigeto Negi10. (1) API Research Laboratories, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan, (2) Frontier Laboratories, Japan, (3) Intellectual Property Department, Japan, (4) Quality Control Section, Kashima Plant, Japan, (5) Production Department, Kashima Plant, Japan, (6) Discovery & Development Research, Japan, (7) Discovery Research Laboratories II, Japan, (8) Scientific Review and Quality Assurance, Japan, (9) Drug Safety Research Laboratories, Japan, (10) Pre-clinical Documentation Department, Japan
ER-40133 is discovered as a novel new NEP/ACE dual inhibitor. The development of practical synthetic route is a quite challengeable since it has six chiral centers and [5,7]-fused bicyclic system. In particular, the center at periposition of its bicyclic lactam moiety and the C9-position are needed to be constructed stereoselectively. In this session, we describe the development of two key chemical processes, diastereoselective methylation of protected 6-oxopipecolic acid ester and stereoselective construction of [5,7]-bicyclic system based on the mechanistic consideration of the stereochemical outcomes.

 

Combinatorial, Parallel and Process Chemistry, Heterocycles, Aromatics, New Reactions and Methodology
8:00 PM-10:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Organic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007