Multigram-Scale Flow Synthesis of the Chiral Key Intermediate of (–)-Paroxetine Enabled by Solvent-Free Heterogeneous Organocatalysis
Sándor B. Ötvös,
,
Institute of Chemistry, University of Graz
(–)-Paroxetine is a selective serotonin reuptake inhibitor which is broadly used for the treatment of depression, anxiety and panic disorder. It is currently manufactured by batch processes of 10?15 reaction steps which typically apply classical resolution methods, chiral auxiliaries, enzymatic asymmetrizations or naturally occurring homochiral starting materials as sources for asymmetry. Catalytic enantioselective transformations have also been harnessed for the synthesis of (–)-paroxetine. These methods require less synthetic steps and provide more direct access to the target API, but their applicability for manufacturing is limited by the low productivity of the catalytic asymmetric key step. Motivated by these limitations, we developed a flow process for the synthesis of the chiral phenylpiperidine key intermediate of (–)-paroxetine. The critical step to introduce asymmetry was a solvent-free enantioselective conjugate addition in the presence of a highly robust heterogeneous organocatalyst. The chiral adduct was processed further via a telescoped reductive amination?lactamization?amide/ester reduction sequence which took advantage of a heterogeneous catalytic hydrogenation approach and the application of neat BH3·dimethylsulfide complex as an efficient reducing agent unprecedented in earlier flow syntheses. The solvent-free or highly concentrated conditions in combination with the remarkably robust catalysts enabled multigram per hour scale production of the chiral target. In addition, the process generated minimal amounts of waste as demonstrated by a cumulative E-factor of 6.
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