Synthesis 2012; 44(20): 3171-3178
DOI: 10.1055/s-0032-1316771
paper
© Georg Thieme Verlag Stuttgart · New York

A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate, the Key Intermediate of Rho–Kinase Inhibitor K-115

Noriaki Gomi
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan, Fax: +81(42)3950312   Email: k-sibuya@kowa.co.jp
,
Akiyasu Kouketsu
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan, Fax: +81(42)3950312   Email: k-sibuya@kowa.co.jp
,
Tadaaki Ohgiya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan, Fax: +81(42)3950312   Email: k-sibuya@kowa.co.jp
,
Kimiyuki Shibuya*
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan, Fax: +81(42)3950312   Email: k-sibuya@kowa.co.jp
› Author Affiliations
Further Information

Publication History

Received: 20 June 2012

Accepted after revision: 10 August 2012

Publication Date:
31 August 2012 (eFirst)

Abstract

A practical synthesis of (S)-tert-butyl 3-methyl-1,4-di­azepane-1-carboxylate has been established for supplying this key intermediate of Rho–kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama–Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)- or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.

 
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