Fluorination methods for drug discovery and development

ABSTRACT

Introduction: The pivotal role that the element fluorine plays in modulating the properties of bioactive molecules is reflected by the growth of its presence in approved drugs. In 1970, approximately 2% of drugs contained fluorine with this number rising to 25% by 2011. The synthetic chemistry regarding incorporation of fluorine into organic molecules has also evolved over this time with a paradigm shift from harsh, toxic, hazardous reagents utilized primarily by specialist vendors to new deoxyfluorination reagents and metal-mediated techniques capable of the precise introduction of fluorine into complex organic substrates under relatively mild conditions.

Areas covered: This review highlights the importance of fluorinated compounds in drug discovery, and provides an overview on the synthetic strategies and methodologies developed to access them both in discovery and development.

Expert opinion: The development of new reagents for the safe and precise regioselective fluorination of biologically relevant compounds particularly in drug discovery remains a contemporary challenge in organic chemistry. However, significant strides have been made with the development of new deoxyfluorination reagents and the emergence of practical metal-mediated fluorination techniques have enabled the goal of efficient late-stage fluorination of drug-like compounds to be realized, and the extension of these methods for PET-labelling is being investigated.

KEYWORDS:

• Fluorine
• deoxyfluorination
• metal-mediated fluorination
• chemistry under microfluidic conditions
• PET (positron emission tomography)
• fluorine-18
• drug discovery

Article highlights

• Of 34 new medicines approved by the FDA in 2014, 12 contained a fluorine atom

• Two synthetic strategies are adopted for the incorporation of fluorine in drug discovery

• Development case studies indicate that the most expensive step involves the introduction of fluorine

• The discovery of DAST and Selectfluor as stable nucleophilic and electrophilic sources of fluorine respectively allowed fluorination to be carried out in standard medchem laboratories

• The emergence of a series of deoxyfluorination reagents in the past several years has alleviated safety concerns, and enabled selective fluorinations to be achieved under mild conditions.

• Mechanistic understanding allows development of a Pd-mediated fluorination of aryl and heteroaryl halides

• Microfluidic techniques allow safe utilization of hazardous fluorinating reagents as well as precise control of reaction conditions

• New viable approaches for the synthesis in the clinic of ¹⁸F-PET tracers are rapidly emerging

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Declaration of interest

P Richardson is an employee of Pfizer Inc. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.