A Concise Formal Synthesis of (−)-Paroxetine

Keywords

(−)-paroxetine - SSRI - formal synthesis - asymmetric hydrogenation

Significance

(−)-Paroxetine is a frequently prescribed selective serotonin reuptake inhibitor (SSRI) for the treatment of various mental illnesses, including depression, obsessive compulsive disorder, panic disorder, and post-traumatic stress disorder. While several synthetic routes have previously been developed toward (−)-paroxetine, many rely on chiral resolution or chiral auxiliaries to access the desired enantiomer. This work features an asymmetric hydrogenation strategy to efficiently afford a known intermediate in the synthesis of this pharmaceutical. This method has the potential to be further applied in the synthesis of additional biologically active molecules containing the same 4-arylpiperidine framework.

 

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Comment

The synthetic route commences with 4-fluoroacetophenone, which first undergoes a Mannich reaction to generate the desired β-amino ketone precursor for the asymmetric hydrogenation. Extensive investigations of the reaction conditions identified the optimal chiral ruthenium catalyst to deliver the (S)-amino alcohol in good yield and enantioselectivity. Acylation of the secondary amine followed by functionalization of the secondary alcohol set the stage for the intramolecular S_N2 reaction to form the arylpiperidine scaffold. Reduction of the methyl ester delivers the known intermediate toward (−)-paroxetine.

 

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Publication History

Article published online:
23 July 2025