Clean Chemistry: Scientists Develop PFAS-Free Process For Fluorinated Pharmaceuticals

Researchers at the University of Amsterdam have unveiled a new method for adding a trifluoromethyl group to molecules containing sulfur, nitrogen, or oxygen, as detailed in their Science paper. This innovative technique avoids the use of PFAS reagents, making it an eco-friendly option for creating pharmaceutical and agrochemical compounds that need this specific group.

Developed by the Flow Chemistry team at the Van 't Hoff Institute for Molecular Sciences under Prof. Timothy Noël, the method was a collaborative effort with experts from Italy, Spain, and the UK. The use of flow chemistry, which involves conducting reactions in small, enclosed tubes, ensures a safer, more controlled process with increased flexibility compared to traditional glassware methods.

Many pharmaceutical and agrochemical compounds, like antidepressants and pesticides, gain significant advantages from having a trifluoromethyl (-CF3) group. This group boosts the hydrophobic nature of the compounds and enhances their metabolic stability, leading to improved effectiveness and reduced dosage requirements.

Traditionally, introducing fluorine into these molecules involves the use of specialized fluorinated reagents, many of which are PFAS compounds and may face future regulations. However, the new synthesis method described in this paper offers a more sustainable alternative by using only cesium fluoride salt as the fluorine source. This PFAS-free approach provides a greener option for producing fluorinated compounds, which has encouraged AstraZeneca scientists to engage in this research.

Furthermore, the new synthesis method allows for the incorporation of the CF3 group through sulfur (S), nitrogen (N), or oxygen (O) atoms. These fluorinated structures impart distinctive properties to drug molecules and agrochemicals, influencing their lipophilicity, resistance to oxidation, and acid-base characteristics.

The paper introduces a highly adaptable microfluidic flow system designed to produce reactive N–, S–, and O–CF3 anions. These anions are generated within a packed bed flow reactor that uses cesium fluoride salt. When precursors containing sulfur, oxygen, or nitrogen are passed through this reactor, they undergo efficient fluorination due to the large surface area of the salt and the improved mixing of the organic intermediates. 

This method also enhances safety by containing all intermediates within the microfluidic system. A key innovation of this system is its integration of an anion generation module with a downstream reaction module. In this setup, the N–, S–, or O–CF3 anions react with suitable substrates in the reaction module to produce the desired pharmaceutical and agrochemical active ingredients.

The integration of the anion generation module with the downstream reactor creates an efficient platform for modifying molecules that feature N–, S–, and O–CF3 groups. This cutting-edge method is set to influence the creation of new pharmaceuticals by improving their characteristics while also enhancing safety and sustainability in production.

The paper details how different anions were combined with various substrates, yielding several fluorinated products significant for pharmaceutical and agrochemical applications. The researchers achieved notably high yields in many cases. Additionally, the operational parameters, such as reaction times, suggest that this method could be effectively implemented in both academic research and industrial settings.