Multigram-scale flow synthesis of the chiral key intermediate of (−)-paroxetine enabled by solvent-free heterogeneous organocatalysis

The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (−)-paroxetine is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free organocatalytic conjugate addition followed by a telescoped reductive amination-lactamization-amide/ester reduction sequence. Due to the efficient heterogeneous catalysts and the solvent-free or highly concentrated conditions applied, the flow method offers key advances in terms of productivity and sustainability compared to earlier batch approaches. The continuous flow synthesis of the chiral key intermediate of (−)-paroxetine is demonstrated via a solvent-free organocatalytic conjugate addition followed by a telescoped reductive amination-lactamization-amide/ester reduction sequence.