Studies on the Mechanism of 1,2-Dihydropyrazin-2-one Ring Formation from Dipeptidyl Chloromethyl Ketone and Its Chemical Properties: Immediate Deamination during Catalytic Hydrogenation

Anna Miyazaki; Yutaka Fujisawa; Kimitaka Shiotani; Yoshio Fujita; Tingyou Li; Yuko Tsuda; Toshio Yokoi; Sharon D. Bryant; Lawrence H. Lazarus; Yoshio Okada

doi:10.1248/cpb.53.1152

Regular Articles

Studies on the Mechanism of 1,2-Dihydropyrazin-2-one Ring Formation from Dipeptidyl Chloromethyl Ketone and Its Chemical Properties: Immediate Deamination during Catalytic Hydrogenation

Anna Miyazaki, Yutaka Fujisawa, Kimitaka Shiotani, Yoshio Fujita, Tingyou Li, Yuko Tsuda, Toshio Yokoi, Sharon D. Bryant, Lawrence H. Lazarus, Yoshio Okada

Author information

Anna Miyazaki
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
Yutaka Fujisawa
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
Kimitaka Shiotani
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
Yoshio Fujita
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
Tingyou Li
High Technology Research Center, Kobe Gakuin University
Yuko Tsuda
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
High Technology Research Center, Kobe Gakuin University
Toshio Yokoi
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
High Technology Research Center, Kobe Gakuin University
Sharon D. Bryant
Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, U.S.A.
Lawrence H. Lazarus
Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, U.S.A.
Yoshio Okada
Faculty of Pharmaceutical Sciences, Kobe Gakuin University
High Technology Research Center, Kobe Gakuin University

Keywords: 1,2-dihydropyrazin-2-one, deuterium substitution, cyclization mechanism, catalytic hydrogenation, deamination

JOURNAL FREE ACCESS

2005 Volume 53 Issue 9 Pages 1152-1158

DOI https://doi.org/10.1248/cpb.53.1152

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Abstract

1,2-Dihydropyrazin-2-one derivatives, which have two aminoalkyl groups at the positions 3 and 6, were found to be efficient tools for the construction of potent, selective and long-acting opioid mimetics. During the course of preparation, we found that the catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove the benzyloxycarbonyl groups resulted in a side reaction. By MS and NMR studies and by preparation of additional 1,2-dihydropyrazin-2-one derivatives, the structure of the by-product was identified as 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. Preparation of additional compounds substituted with deuterium provided us with sufficient information to confirm the structure of the product and to support a cyclization mechanism in its formation.

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