Establishment of the Continuous Synthesis of Ceramide (D-erythro-CER [NDS]) via Oxo-Tethered Ruthenium Complex-Catalyzed Asymmetric Transfer Hydrogenation Using Pipe-Flow Reactor

Abstract

The ceramide compound, N-((2S,3R)-1,3-dihydroxyoctadecan-2-yl)stearamide (D-erythro-CER [NDS]), plays a critical role for the barrier function of mammalian skin. This material is widely used for various cosmetics and drugs for the skin care purpose. The development of an efficient synthetic route for optically active D-erythro-CER [NDS] using continuous flow synthesis and purification techniques is described. The route proceeds through asymmetric transfer hydrogenation of methyl 2-acetamido-3-oxooctadecanoate in a Pipes-in-Series flow reactor with oxo-tethered ruthenium complex “DENEB^®”-catalyzed dynamic kinetic resolution as a key process. The subsequent continuous processes including the crystallization and crystal separation were also investigated. This synthesis was accomplished without isolating any intermediates, allowing for the consecutive synthesis and purification on a production scale.