Enantioselective Gram‐Scale Synthesis of Rasagiline via Chiral Phosphoric Acid‐Catalyzed Reduction of Cyclic Imine

This study presents a practical and scalable enantioselective synthesis of rasagiline mesylate, a key Parkinson's disease drug, using asymmetric transfer hydrogenation of a challenging cyclic imine intermediate. By leveraging a chiral phosphoric acid (CPA) catalyst and Hantzsch ester, the authors achieved high enantioselectivity (>96% ee) without relying on optical resolution. The method also shows broad applicability to related substrates, offering a valuable advance in chiral amine synthesis.

Abstract

Rasagiline mesylate is a monoamine oxidase B inhibitor used clinically for treating Parkinson's disease. Conventional synthesis relies on optical resolution, which limits efficiency and scalability. To overcome these challenges, we developed an enantioselective synthesis route using asymmetric transfer hydrogenation (ATH) of a cyclic propargyl imine intermediate. Although cyclic imines are difficult to reduce due to their rigid structures, this challenge was overcome using a chiral phosphoric acid catalyst with a Hantzsch ester, affording chiral amines in high yield and enantioselectivity. The method was successfully scaled to the gram level, affording rasagiline mesylate with >96% enantiomeric excess. Furthermore, this approach showed broad substrate compatibility, underscoring its general utility in the asymmetric reduction of cyclic imine derivatives. Our strategy offers a practical and scalable alternative to existing methods for the synthesis of rasagiline and structurally related optically active amines.