The first detailed description of the Lewis acid-catalyzed racemization of (R)-ketamine is reported. A process for racemization of the undesired (R)-ketamine enantiomer produced from the resolution for preparing the NMDA receptor antagonist (S)-ketamine was developed in quantitative yield with 99% chemical purity in the presence of a Lewis acid at 150 °C. Varying degrees of racemization were observed in the presence of various frequently used Lewis acids separately, and the catalytic efficiencies were arranged as follows: MgCl2 ≈ AlCl3 > FeCl3 > ZnCl2 > BF3 > CaCl2. The racemized ketamine was subsequently resolved using l-(+)-tartaric acid to obtain (S)-ketamine in 41% yield with 99.5% ee. Such a concise and cost-efficient approach for the racemization can be industrially useful to recycle the waste (R)-ketamine enantiomer into the resolution process to obtain (S)-ketamine.

An efficient tandem route to the synthesis of 2,2a 1 ,4-triazacyclopenta[cd]indene derivatives of the cyclazine family has been developed. The target compounds were obtained in moderate to good yields by an ytterbiumA C H T U N G T R E N N U N G (III) triflate/palladium(II) acetate-catalyzed three-component domino reaction involving a palladium-catalyzed intramolecular aarylation of an a-aminocarbonyl functionality. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocyclic skeletons containing the privileged imidazoA C H T U N G T R E N N U N G [1,2-a]pyridine structure.

An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.