Technology assisted methodology in the synthesis of fluoropharmaceuticals

The development of fluorination methodologies has been bolstered by the use of F-18 labeled ligands in positron emission tomography (PET). Fluorination chemistry has taken great strides developing new and efficient aliphatic and aromatic fluorination methods for the incorporation of F-19 and F-18. Fluorinated compounds are used extensively in medicine and drug design as they have been developed to treat a range of disorders and conditions such as cancer, CNS, antiviral, anesthetics, infection and inflammation. Methods for the installation of fluorine have improved dramatically over the last ten years, aromatic fluorination whether nucleophilic or electrophilic aromatic substitution remains challenging. The importance of the nitro leaving group for nucleophilic aromatic fluorine substitution (fluorodenitrations), the need for late stage selective ipso-substitution of the nitro group, and subsequent fluorination of nitroarenes will be discussed.;A growing number of pre-clinical and investigation agents for PET imaging possess (F-18) fluoroalkyl chains. These include the mitochondrial complex (MC-1) inhibitors RP1005, and BMS747158-02, which were developed for myocardial perfusion imaging, the nicotinic receptor targeting agent nifrolidine and the dopamine receptor targeting agent fallypride. A key to developing CNS targeted imaging agents is optimizing lipophilicity of the drug to maximize blood brain barrier penetration (and, conversely for cardiovascular agents) and this typically requires re-syntheses, as the addition of even a single methylene spacer can have a profound impact on transport properties. Microwave and microfluidic technology have proven extremely useful tools for organic synthesis, by expediting reactions, decreasing by-product formation and increasing atom efficiency. Radiochemistry facilities have pushed towards fully automated radiosynthesis modules to lower exposure and maximize reproducibility of radioligands. With this backdrop we have been investigating means to develop efficient coupling methods, which (1) allow effective fluorination of &ohgr;-alkynyl sulfonates with subsequent coupling of these hydrocarbon chains onto readily available arenes (2) where chain length and hybridization can be modified at ease and (3) develop a fully automated synthesis which can adapt to a continuous flow process. The incorporation of technology assisted organic synthesis for the development of fluoropharmaceuticals and PET ligands will be discussed.