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

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

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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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