Fluticasone and Related Examples

The fluoromethyl moiety has proven useful in a range of pharmaceutically relevant targets and agrochemically-significant compounds. One of the first examples of the use of bromofluoromethane in the synthesis of a commercial product is in the fluoromethylation of a thioacid to manufacture fluticasone propionate by Glaxo (Eq. 1). Subsequently, BFM has been shown to be generally useful in accessing other fluticasone-related molecules – including fluticasone furoate by GlaxoSmithKline (Eq. 2).Other companies have demonstrated the utility of BFM to construct related scaffolds including Chiesi Farmaceutici’s pyrrolidine-containing glucocortosteroids (Eq. 3) and biaryl ether-containing glucocorticoids from Pfizer (Eq. 4).

PET Imaging Examples

Bromofluoromethane (BFM) has also proven useful for accessing PET imaging molecules. BFM can be cross coupled with boronic esters to access fluoromethyl aromatic compounds (Eq. 5). Additionally, alkylation using phenolic nucleophiles such as the protected tyrosine derivative shown below provides a PET imaging precursor in good yield (Eq. 6).

Alkylation of Phenolic Compounds

Flouromethylation of phenols with bromofluoromethane (BFM) has proven useful to provide access to a variety of compounds. Acadia Pharmaceuticals reported the synthesis of cannabinoid CB2 receptor active compounds using precursors containing fluoromethyl ethers (Eq. 7). Astrazeneca synthesized oxabispidine compounds for treatment of cardiac arrhythmias derived from flouromethyl-alkylated aldehyde derivatives (Eq. 8).

Oxime Alkylation

Bromofluoromethane (BFM) can be used to alkyl other oxygen nucleophiles including oximes as shown below (Eq. 9).

Enolate Alkylation

Bromofluoromethane (BFM) has also been employed for fluoromethylation of enolates. Takeda Pharmaceutical Company reported the alkylation of cyanoazetidine using LDA in good yield to access JAK inhibitors (Eq. 10).

Incorporation into Heterocylces

Bromofluoromethane (BFM) can also be utilized to alkylate complex heterocycles. Francotte and co-workers used BFM to construct new potentiators of AMPA receptors (Eq. 11). Sinochem utilized BFM to access the pyrazole derivative as potential broad spectrum insecticide  (Eq. 12).