Synthesis of new fluorine-based drugs at lightning speed

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The research team led by Professor Dong-Pyo Kim and Jeong-Un Joo (Department of Chemical Engineering at POSTECH), and Professor Heejin Kim and Hyune-Jea Lee (currently a researcher at Samsung Institute of Advanced Technology) from the Department of Chemistry at Korea University has successfully developed a new method to synthesize trifluoromethyl intermediate (-CF3) from fluoroform (CHF3). It involves the use of a special reactor capable of ultra-fast mixing between gas and liquid. This method offers promising prospects for the synthesis of new novel fluorine-based drugs. The research was published in nature communications.

Fluoride is not found in its pure form naturally, but exists solely in the form of various chemical compounds. Sodium fluoride, a fluoride-containing compound, is used as an ingredient in toothpaste because of its ability to coat teeth and prevent cavities. Recent studies have highlighted the potential of fluoride-containing synthetic drug molecules, as they possess high permeability in cell membranes of diseased tissues and exhibit strong binding affinity against proteins. Consequently, there is a growing interest in the development of drugs containing fluoride.

There are several approaches to synthesizing trifluoromethyl, but the most cost-effective method is to replace a hydrogen atom of the fluoroform, a simple precursor, with another element or functional group. However, the gaseous fluoroform is volatile, which makes it difficult to mix with liquids and shows low reactivity. In addition, it breaks down instantly, which requires the addition of a substance that can react with it. Unfortunately, this process can cause unwanted chemical reactions that lead to a low yield of trifluoromethyl.

To address the challenge of synthesizing trifluoromethyl from fluoroform, the research team developed a new gas-liquid reactor with a zigzag-shaped channel and highly permeable non-porous membranes sandwiched between the upper and lower channels. This setup allowed for the eddying and mixing of superbase, a liquid used for dehydrogenation, and fluoroform gas within the reactor. By breaking the fluoroform bubbles into smaller pieces to increase the contact area between the gas and the liquid, the team was able to produce trifluoromethyl anion (CF₃^–). Unlike traditional approaches, they produced a fluoride intermediate effectively without the need for stabilizers or additives.

The research team synthesized a fluorine-based compound by immediately adding a compound that will react with the intermediate fluoride anion. The entire process, which involved the generation of a fluorine anion intermediate from fluoroform, took place in one second. The team maximized the formation of a trifluoromethyl anion, which is known to be short-lived, and quickly facilitated the subsequent reaction before the intermediate decomposed. This method allowed to improve the performance of fluorine-based compounds and introduced a robust technique for the synthesis of fluorine-based drugs.

The research findings have significant implications for industrial applications in the economically efficient synthesis of fluoride compounds, making them more practical and contributing significantly to studies on various unstable intermediates.

The study was conducted with support from the National Research Foundation of Korea.