An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)-α-Methylbenzylamine as Chiral Auxiliary

We present a new synthesis of ritlecitinib, employing asymmetric reductive amination via a chiral auxiliary group combined with intramolecular amide formation. This method employs a titanium(IV) ethoxide/sodium tetrahydroborate (Ti(OEt)₄/NaBH₄) reductive system to achieve a one-pot condensation-reduction of the ketone-amino acid derivative with (S)-α-methylbenzylamine, resulting in an 85% yield of the di-amino acid derivative with a diastereomeric ratio of 86:14. The incorporation of a chiral auxiliary substantially enhances the diastereopurity. Subsequently, acetic acid-mediated cyclization then forms the δ-lactam in 60% yield. This lactam is converted to ritlecitinib via a five-step sequence in 62% overall yield. This approach effectively circumvents the use of precious metal catalysts or hazardous reagents for constructing the chiral piperidine moiety, which were essential components in prior synthetic route.