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

Area of Science:

• Organic Chemistry
• Medicinal Chemistry

Background:

• Ritlecitinib is a Janus kinase (JAK) inhibitor used for treating certain autoimmune diseases.
• Previous synthetic routes for ritlecitinib often relied on precious metal catalysts or hazardous reagents for constructing the chiral piperidine moiety.

Purpose of the Study:

• To develop a new, more efficient, and safer synthetic route for ritlecitinib.
• To circumvent the use of precious metal catalysts and hazardous reagents in the synthesis.

Main Methods:

• Asymmetric reductive amination using a chiral auxiliary group.
• One-pot condensation-reduction with a titanium(IV) ethoxide/sodium tetrahydroborate (Ti(OEt)₄/NaBH₄) system.
• Acetic acid-mediated cyclization to form a δ-lactam intermediate.

Main Results:

• Achieved an 85% yield of the di-amino acid derivative with a diastereomeric ratio of 86:14 using the developed method.
• The chiral auxiliary significantly improved diastereopurity.
• Synthesized the δ-lactam in 60% yield.
• Completed the ritlecitinib synthesis from the lactam in a five-step sequence with an overall yield of 62%.

Conclusions:

• The new synthetic approach for ritlecitinib is efficient and avoids problematic reagents.
• This method provides a safer and more sustainable alternative for producing the chiral piperidine core of ritlecitinib.
• The developed synthesis offers a valuable alternative for the large-scale production of ritlecitinib.