Nov 21, 2019PRESS RELEASE

Development of a novel method for synthesizing pharmaceutical compounds containing fluorine atoms using sequential organic synthesis reactions

Keyword:RESEARCH

OBJECTIVE.

Associate Professor Keiji Mori of Tokyo University of Agriculture and Technology's Graduate School of Engineering, Department of Applied Chemistry; Professor Akihiko Takayama of Gakushuin University's Department of Chemistry; and Professor Masahiro Yamanaka of Rikkyo University's Department of Chemistry succeeded in the stereoselective synthesis of polycyclic compounds (spiroisochromans) with a trifluoromethyl group (-CF3) by combining carbon-hydrogen bond transformation, which is a difficult chemical reaction to generate, with a basic organic reaction. Their result is expected to open up pathways for supplying new drug candidate compounds that could not be synthesized using previous methods.

The study was published in the American Chemical Society's "Organic Letters" journal (March 19 issue).

Current state

“Organic fluorine compounds,” in which a fluorine group (fluoro group, trifluoromethyl group) is introduced to a candidate compound, have attracted attention in the pharmaceutical field recently. The main reason for this is that when hydrogen atoms in drug molecules are replaced with fluorine atoms, it changes their absorption, metabolism, excretion, and distribution in the human body, often leading to major improvements in pharmacological activity. Among the organic fluorine compounds, those such as isochroman or isoquinoline, which combine a fluorine group with a structural unit containing crude drugs or other substances, are a molecular group expected to possess unique and unprecedented pharmacological activities. While they have high utility, conventional synthesis methods have problems such as their use of oxidizing agents, which become waste products after reactions. Therefore, there has been a strong demand for novel synthesis methods.

Research structure

The study was conducted by Satoka Tamura and Associate Professor Keiji Mori of Tokyo University of Agriculture and Technology's Graduate School of Engineering, Department of Applied Chemistry; Eriko Kitamura and Professor Akihiko Takayama of Gakushuin University's Department of Chemistry and natural sciences research; and Assistant Professor Ryo Tsutsuji and Professor Masahiro Yamanaka of Rikkyo University's Department of Chemistry. In addition, the study was funded by grants-in-aid for basic scientific research (B) 26288053 and 17KT0011, the Uehara Memorial Foundation, and the Naito Foundation.

Reaserch results

The objective of this study was to combine a method of carbon-hydrogen bond transformation that does not require a transition metal catalyst or external oxidizing agent, with the Friedel-Crafts reaction, which is a general organic reaction, to develop a novel method of synthesizing isochromans containing a trifluoromethyl group and that have a spiro ring structure (spiroisochroman), such as is found in many pharmaceutical products. The key to achieving this reaction was designing an appropriate reactive molecule that would advance two organic reactions sequentially. After various attempts, the planned sequntial reaction was realized using as the raw material an ether with a highly reactive aromatic ring and a trifluoromethyl ketone site in the molecule. The method developed in this study can also be used to control the arrangement of substituents (steroselective synthesis), which has been in strong demand for applications in the pharmaceutical field.

Future prospects

While the current study focused on isochromans, this methodology can also be used to synthesize structures containing nitrogen atoms (isoquinolines) and those composed only of carbon atoms (tetralins), which are also expected to have strong pharmacological effects. This method is expected to lead to never before seen drug candidate compounds.

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