Novel Approach toward 3,3-Difluoropiperidines from Easily Available Starting Materials and Synthesis of a New Phosphodiesterase Inhibitor

Abstract

A novel methodology for the synthesis of 3,3-difluoropiperidines has been developed. The target compounds are prepared in three steps using a robust protocol and simple starting materials. The incorporation of the fluorine is achieved by using the cheap and easily available ethyl 2-bromo-2,2-difluoroacetate as building block. Using this methodology, a new potent in vitro phosphodiesterase 2A (PDE2A) inhibitor containing the functionalized fluorinated piperidine scaffold has been prepared.

Aza‐Heterocyclic Building Blocks with In‐Ring CF2‐Fragment

“…Significant improvement of the aforementioned approach was offered by Giacoboni et al (Scheme 68). [147] The devised 3-step protocol involved easily available reagents to achieve a key common intermediate 407, which is then alkylated with a substituent of choice giving 424. The nitriles were next reduced to amine triggering cyclization process and affording already unprotected piperidines 425 allowing easy further functionalization.…”

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

“…Among the variety of aromatic and saturated structures, the piperidine ring has a special role, as it is the most widely occurring form of nitrogen in FDA-approved drugs [3]. The ability of fluorine atoms to modify basicity, lipophilicity, as well as the hydrogenbonding properties of amines [4,5] makes fluorinated piperidines [6,7] attractive targets in medicinal chemistry [8,9]. Previous efforts were mainly focused on the synthesis of monoand difluorinated compounds.…”