Research and Development on the Manufacturing Process of Dexmedetomidine from Chiral Precursors: Resolution–Racemization–Recycle Synthesis Strategy

The present work describes the development of a new synthetic route to dexmedetomidine (1), widely used in hospital practice as a versatile anesthetic, free of respiratory distress effects. The conventional approach to the manufacture of compound 1 rests on the resolution of racemic medetomidine (2). 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 (5), to be resolved at preliminary steps instead of resolution of dexmedetomidine 1 itself. The resolved acid (S)-enantiomer 4 is then used in the synthesis of 1 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 4 included the preparation of sulfur ylide 19 from acid chloride 16 and dimethylsulfoxonium methylide 18, transformation of compound 19 into α-bromoketone 21, and its subsequent transformation to salts 25a–25j. 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 21 with sodium azide, followed by hydrogenation of the resulting azidoketone 30. The Marckwald cyclization of aminoketone salts 25 with potassium thiocyanate afforded a dexmedetomidine thio derivative 26, the desulfurization of which gave the (S)-enantiomer-enriched target product 1 in high yield. Excellent yields of the racemic acid 5 recycled after resolution and a high percentage recovery of the commercially available chiral amine 11 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 (2). In addition, the exclusion of expensive Rh catalysts and chiral ligands, which are used in current methods, considerably decreased the manufacturing cost of 1.