Synthesis of Enantiopure Piperidines on Industrial Scale

Keywords

chiral piperidines - photochemical decarboxylative fluorination - flow chemistry - process chemistry

Significance

It is estimated that 20 % of all known commercial pharmaceuticals contain fluorine to increase the metabolic stability, refine the potency, or improve the physicochemical properties of drugs. Additionally, piperidines make up an interesting class of structures in drug discovery because their high stereochemical definition offers precise chemical spaces for protein interaction. The authors describe the enantiopure synthesis of a chiral trans-substituted fluoropiperidine on an industrial scale (401 g of final material provided).

Comment

The synthesis is commenced by the hydrogenation of a symmetric pyridine in flow followed by kinetic resolution to afford the meso-fumarate salt. After Cbz protection, biocatalytic desymmetrization yields the cis-monoacid, which is subjected to a photochemical decarboxylative fluorination in flow. The two resulting diastereomers are separated by chiral SFC and the desired trans-diastereomer is saponified to give the target piperidine with excellent diastereomeric and enantiomeric purities.

Publication History

Article published online:
20 December 2024