Chemistry of Amide Nitrogen Modification by Fluoro Substituents

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06483
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: YAMASAKI RYU 昭和薬科大学, 薬学部, 准教授 (90453844)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アミド / フッ素 / 立体構造 / 置換基効果

Outline of Final Research Achievements

In this study, synthetic methods for compounds bearing fluorine substituents (fluorocarbons) into amide compounds was established and their structural properties were analyzed. Specifically, synthetic methods for each of the following compounds was developed; (1) amide compounds with multiple bonds as scaffolds for introduction of fluorine, (2) amide compounds with pentafluorophenyl rings, (3) amides with monofluoromethyl groups, (4) amides with difluoromethyl groups, and (5) amide compounds with monofluoromethyl groups. Then, their respective structural characteristics were analyzed in detail using X-ray crystallography, NMR, and DFT calculations. As a result, the electronic repulsion and electron-withdrawing nature of fluorine atoms were found to be significantly influencing the conformation and bond angles of the amide.

Free Research Field

有機合成化学、有機構造化学

Academic Significance and Societal Importance of the Research Achievements

脂溶性向上や代謝安定性などの物性向上を目的に、直近10年で承認された医薬品の2割以上が1つ以上のフッ素原子をもつ。一方でフッ素置換基をアミド化合物に導入した場合の構造特性はそれまで系統的に検討されていなかった。本研究はフッ素をもつアミド化合物の合成法を確立し、その構造特性を明らかとしたことで、医薬化学における化合物デザインに貢献するものと考える。また本研究の遂行においてアミドに多重結合をもつ化合物の構造特性、昇華によりon-off型でスイッチング可能な分子、芳香族求核置換や光によるフッ素芳香族特有の変換反応等、今後の多様な研究展開に繋がる知見が得られた。