Fluorination methods in drug discovery

Abstract

Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that the fluorine atom can impart to targets of medicinal importance, such as a modulation of lipophilicity, electronegativity, basicity and bioavailability, this latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, nucleophilic, electrophilic and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp 3 , sp 2 , and sp carbon atoms) will be studied in late-stage fluorination reaction strategies. The omniphobicity/lipophilicity and electrostatic interactions can be considered among the most prominent effects. Thus, introducing fluorine into an organic compound can significantly alter its biological properties.One other subtle but important effect of introducing fluorine into the backbone of a medicinal target is the inflection of acidity and basicity of the parent compound 4 , which can change, inter alia, the binding affinity, and bioavailability. Highly basic groups can have a detrimental effect on the bioavailability of a drug. Thus introducing a fluorine atom next to a basic group can reduce its basicity, enhancing its membrane permeability, and increasing bioavailability. Although the replacement of hydrogen for fluorine does not have a profound steric influence, electrostatic interactions with other groups can change conformations significantly. The replacement of hydrogen for fluorine on aromatic rings is a well-known strategy to decelerate oxidative metabolic processes by Cytochrome P450 monooxygenases. In this respect, the electron-withdrawing properties of fluorine on aromatic rings, which can slow down hydrolytic metabolism, alter reaction rates and stability of intermediates. Fluorine substitution on aromatic rings is also known to increase binding affinity, as a result of enhancing electrostatic interactions.However, it is difficult to predict the influence of fluorine substitution on the overall profile in a given situation.As numerous reports attest 1 , the number of marketed drugs that contain a fluorine atom has increased rapidly. As of 2009, the FDA-had approved >140 fluorine-containing drugs. This review article is intended to present new synthetic methodologies 9 for accomplishing fluorination reactions on molecules (drugs/prodrugs) with pharmacological activity. It is not our aim (Figure 3). would be beneficial to the syntheses. 3a.-Conversion of C Ar -H into C Ar -F BondsXu and co-workers 38 have developed an ortho C-H bond fluorination of 2-phenoxyl pyridine derivatives through a palladium-catalyzed reaction v...

Pd-Catalyzed Mizoroki-Heck Reactions Using Fluorine-Containing Agents as the Cross-Coupling Partners

“…The products 52 proved to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group could be exclusively attacked by nucleophiles under defined conditions, making these simple cores attractive for covalent drug discovery [60]. Pd-Catalyzed intramolecular cyclization of O- (3,3-difluoroallyl)phenyl triflate (41) and 3,3-difluoroallyl ketone oximes (46) by the Mizoroki-Heck reactions of the polarized carbon-carbon double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme 7) [45,57,58]. In the first step of the reactions, an arylpalladium or aminopalladium intermediate (42 or 47) bearing a 2,2-difluorovinyl group is formed from 41 or 46, respectively.…”

“…There have been as many as 25% of pharmaceuticals and 30-40% of agrochemicals on the market containing at least a single fluorine atom [41]. Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51].…”

“…Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51]. In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51].…”

“…It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51]. In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51]. The incorporation of fluorinecontaining fragments into organic frameworks by Pd-catalyzed Mizoroki-Heck reactions has proved to be the simplest and most convenient pathway to build diverse alkenes bearing fluorinated functionalities.…”

“…Pd-Catalyzed intramolecular cyclization of O- (3,3-difluoroallyl)phenyl triflate (41) and 3,3-difluoroallyl ketone oximes (46) by the Mizoroki-Heck reactions of the polarized carbon-carbon double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme 7) [45,57,58]. In the first step of the reactions, an arylpalladium or aminopalladium intermediate (42 or 47) bearing a 2,2-difluorovinyl group is formed from 41 or 46, respectively.…”