Chemists successfully synthesize fluorinated pharmaceutical and agrochemical compounds without PFAS

Chemists at the University of Amsterdam have developed a method for adding a trifluoromethyl group to a series of molecules attached to a sulfur, nitrogen or oxygen atom. Their procedure, published in Scienceavoids the use of PFAS reagents. It thus offers an environmentally friendly synthesis route for pharmaceutical and agrochemical compounds that rely on the presence of the trifluoromethyl group.

This simple and effective method was developed by the Flow Chemistry Group at the Van ‘t Hoff Institute for Molecular Sciences, led by Professor Timothy Noël, in cooperation with researchers from Italy, Spain and the UK, from both academia and industry. Applying the principles of flow chemistry, where reactions take place in closed systems of small tubes, allows for safe and controlled chemistry. It also offers greater versatility and flexibility compared to more common procedures using traditional chemical glassware.

More environmentally friendly

Many pharmaceutical compounds (such as antidepressants) as well as agrochemical compounds (such as pesticides) benefit from the presence of a trifluoromethyl (-CF₃) group. It improves hydrophobicity and increases metabolic stability, thereby improving efficacy and reducing the required dose or concentration.

To introduce fluorine atoms into these molecules, their synthesis often requires tailor-made fluorinated reagents. Many of these are part of the PFAS family of compounds and will therefore be subject to future legislation. The synthesis protocol presented in the article offers a viable alternative because it only requires cesium fluoride salt as a fluorine source. Such PFAS-free synthesis of fluorinated agents can provide a more environmentally friendly option for the synthesis of pharmaceutical compounds, which motivated AstraZeneca scientists to participate in the research.

In addition, the new synthesis protocol allows the coupling of CF₃ group by a sulfur (S), nitrogen (N) or oxygen (O) atom. These fluorinated units confer unique characteristics to drug molecules and agrochemicals, affecting their lipophilicity, resistance to oxidation and acid-base properties.

Integrated flow system

The paper presents a versatile microfluidic flow module to generate reactive N–, S– and O–CF₃ The anions are prepared in a fixed-bed reactor containing the cesium fluoride salt. The appropriate precursors (containing S, O or N) are then fed through this reactor. They are fluorinated with high efficiency due to the large surface area of ​​the salt in the fixed bed as well as the improved mixing of the organic intermediates. Importantly, this approach also offers increased safety as all intermediates formed are contained within the microfluidic system.

Another important feature of the system is the integration of the anion generation module with a downstream reaction module. There, the N–, S– or O–CF₃ Anions react with suitable substrates to obtain pharmaceutical and agrochemical active ingredients as desired end products.

Implementation in an academic and industrial context

In combination, the anion generator module and downstream reactor provide a streamlined platform for the derivatization of molecules bearing N–, S– and O–CF₃ motives. This innovative approach is poised to impact the development of new pharmaceutical drugs by improving their properties while enhancing the safety and sustainability of their production processes.

In their paper, the researchers describe the combination of various anions with a range of substrates, resulting in multiple fluorinated products relevant for pharmaceutical and agrochemical syntheses. In many cases, the research team was able to report very satisfactory yields. Furthermore, the operational parameters (e.g., reaction times) offer good prospects for real-world implementation in an academic as well as industrial context.