Rezatomidine

The present work describes the development of a new synthetic route to dexmedetomidine, widely used in hospital practice as a versatile anesthetic, free of respiratory distress effects.The conventional approach to the manufacture of compound dexmedetomidine rests on the resolution of racemic medetomidine.However, besides a low recovery of the (S)-enantiomer (∼0.2 kg from one kg of the racemate), the classical resolution suffers from production of chiral waste enriched in levomedetomidine (R-enantiomer), which could not be racemized in a safe and practically applicable manner.We proposed a new precursor for dexmedetomidine, 2-(2,3-dimethylphenyl)propionic acid, to be resolved at preliminary steps instead of resolution of dexmedetomidine itself.The resolved acid (S)-enantiomer (S)-2-(2,3-Dimethylphenyl)propionic acid is then used in the synthesis of dexmedetomidine and the (R)-enantiomer-enriched chiral waste are readily racemized in a simple, safe, and scalable manner and used again.Further synthesis steps involving (S)-acid included the preparation of sulfur ylide from acid chloride and dimethylsulfoxonium methylide, transformation of (3S)-1-[dimethyl(oxido)-sulfanylidene]-3-(2,3-dimethylphenyl)butan-2-one into α-bromoketone, and its subsequent transformation to salts.The ''azide route'' was found to be the optimum one for the preparation of aminoketone, providing the product with acceptable enantiomeric purity, and included the reaction of bromoketone with sodium azide, followed by hydrogenation of the resulting azidoketone.The Marckwald cyclization of aminoketone salts with potassium thiocyanate afforded a dexmedetomidine thio derivative, the desulfurization of which gave the (S)-enantiomer-enriched target product dexmedetomidine in high yield.Excellent yields of the racemic acid recycled after resolution and a high percentage recovery of the com. available chiral amine used for resolution, as well as preliminary enrichment of the crude product with the (S)-enantiomer, allowed us to decrease the amount of chiral waste almost 4-fold compared to the classical resolution of racemic medetomidine.In addition, the exclusion of expensive Rh catalysts and chiral ligands, which are used in current methods, considerably decreased the manufacturing cost of dexmedetomidine.