Fluorine in Medicinal Chemistry.


As a synthetic organic chemistry I  didn’t need to introduce a single fluorine atom in any of the molecules I synthesised over the years. That all changed when I moved into medicinal chemistry. In the project in which I am currently involved we have introduced up to four fluorine atoms in molecules with molecular weights between 350 and 380.

Fluorine is a hot topic in Drug Discovery and this is not only reflected in the recently published book “Fluorinated pharmaceuticals: advances in medicinal chemistry”, to which a member of staff of the SDDC contributed, but also in a recent article which reviews the effects that the strategic introduction of fluorine can have on potential drug candidates, influencing conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways and pharmacokinetic properties.

Thanks to the advances in fluorine chemistry we are nowadays presented with a variety of reagents for selective introduction of fluorine or fluoroalkyl groups into specific locations. A recent new synthetic methodology gives access to pyrazoles bearing diverse fluoroalkyl groups, targets that were, till now, difficult to prepare.

The difficulty, up to now, of their preparation is sketched below, and it was mainly due to the trouble in handling and preparing the polyfluoroalkyl β-diketone precursors.

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The new procedure developed by Leroux and co-workers uses the unprecedented reaction between activated fluoroalkyl amino reagents, easily prepared from fluroolefines, and azines.

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Treatment of a fluoroalkyl amino reagents with a Lewis acids generates the corresponding iminium salt which reacts with fluorinated azines to form vinamidinum intermidiates. The latter can then easily cyclize to 3,5-bis(fluroalkyl)-1H-pyrazoles upon treatment with concentrated HCl.

In this article the authors prepare 14 different pyrazoles in moderate to excellent yields (see Table below), in one-pot, without isolation of any of the intermediates, giving a quick access to pyrazoles that bear two fluoroalkyl functionalities.

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Blog written by Carol Villalonga

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