Chemists on the University of Amsterdam have developed a way to furnish a variety of molecules with a trifluoromethyl group attached to a sulphur, nitrogen or oxygen atom. Their procedure, which has just been published in Science, avoids using PFAS reagents. It thus provides an environmentally friendly synthesis route for pharmaceutical and agrochemical compounds that depend on the presence of the trifluoromethyl group.
The simple and effective method was developed on the Flow Chemistry group on the Van ‘t Hoff Institute for Molecular Sciences led by Prof. Timothy Noël, in cooperation with researchers in Italy, Spain and the UK, each from academia and industry. Applying the principles of flow chemistry, where reactions happen in closed systems of small tubes, makes for secure and controlled chemistry. It also offers greater versatility and suppleness over more common procedures using traditional chemical glassware.
Environmentally more friendly
Many pharmaceutical compounds (similar to anti-depressants) in addition to agrochemical compounds (similar to pesticides) profit from the presence of a trifluoromethyl (-CF3) group. It enhances hydrophobicity and increases metabolic stability, thus improving efficacy and lowering the required dose or concentration.
To introduce the fluorine atoms in these molecules, their synthesis often requires bespoke fluorinated reagents. Lots of these are among the many family of PFAS compounds and thus will face future laws. The synthesis protocol now presented within the Science paper provides a viable alternative because it only requires caesium fluoride salt because the fluorine source. Such PFAS-free synthesis of fluorinated agents can provide an environmentally more friendly option for the synthesis of pharmaceutical compounds, which motivated scientists from AstraZeneca to take part in the research.
As well as, the brand new synthesis protocol enables coupling of the CF3 group through a sulphur (S), nitrogen (N) or oxygen (O) atom. Such fluorinated motifs confer unique features to drug molecules and agrochemicals, impacting their lipophilicity, oxidation resistance, and acid-base properties.
Integrated flow system
The Science paper presents a flexible microfluidic flow module for generating reactive N-, S- and O-CF3 anions. These are prepared in a packed bed flow reactor containing the caesium fluoride salt. Appropriate (S, O or N containing) precursors are then led through this reactor. They’re fluorinated with high efficiency because of the high surface area of the salt within the packed bed as well and the improved mixing of the organic intermediates. Importantly, this approach also offers enhanced safety as all formed intermediates are contained inside the microfluidic system.
One other vital feature of the system is the mixing of the anion generating module with a downstream response module. There, the N-, S- or O-CF3 anions react with appropriate substrates to attain pharmaceutical and agrochemical energetic ingredients as the specified end products.
Implementation in a tutorial and industrial context
Together, the anion generator module and the downstream reactor provide a streamlined platform for the derivatization of molecules bearing N-, S- and O-CF3 motifs. This revolutionary approach is poised to affect the event of recent pharmaceutical drugs by enhancing their properties while improving safety and sustainability of their production processes. Of their Science paper, the researchers report the mixture of varied anions with a variety of substrates, leading to multiple fluorinated products with relevance to pharmaceutical and agrochemical syntheses. In lots of cases the research team was in a position to report very satisfactory yields. Furthermore, the operational parameters (e.g. response times) offer a great prospect for actual implementation in a tutorial in addition to an industrial context.
