First Synthesis and Utilization of Oripavidine – A Concise and Efficient Route to Important Morphinans and Apomorphines by Attila Sipos* a ), Sa ´ndor Bere ´nyi a ), and Sa ´ ndor Antus a ) b ) a )Department of Organic Chemistry, University of Debrecen, P.O. Box 20, HU-4010 Debrecen (fax: þ 36-52-512836, e-mail: asipos@puma.unideb.hu) b )Research Group for Carbohydrates of the Hungarian Academy of Sciences, P.O. Box 55, HU-4010 Debrecen The synthesis and transformation of oripavidine (8) offer an efficient and simple route to highly active dopamine agonist apomorphines and a variety of important 14b-hydroxy-morphinan derivatives. Natural origin thebaine (6), the starting compound of the procedure, was converted into its N-{[1,2- bis(ethoxycarbonyl)hydrazinyl]methyl} counterpart. l-Selectride was found to be an efficient agent to perform a one-pot O- and N-deprotection at positions 3 and 17, respectively. Introduction. – The synthesis of high affinity dopamine agonists is one of the main directions of the chemistry of aporphines. It is a general observation that the N- substitution of potent compounds could further improve their binding affinities and selectivities to D 1 or D 2 receptor subtypes 1 ) . In the Figure, the structure and D 2 affinity of some important apomorphines, 1 – 5, are presented. Apomorphine hydrochloride (1 · HCl) is the active drug substance of some pharmaceutical products acting via its dopaminergic potency. Compounds 2 – 4 are frequently used in the pharmacological studies associated with the activation of the dopamine system. These N-substituted derivatives are traditionally prepared with the acid-catalyzed rearrangement of previously N-substituted morphinans. Our research group explored the opportunities of a one-step synthesis of 2-O- and 2-S-substituted aporphines from appropriate morphinandienes [2]. This shortened methodology still comprises at least five steps from natural thebaine (6), and 19 – 23% of overall yields were achieved. In Figure. Some important D 2 agonists Helvetica Chimica Acta – Vol. 92 (2009) 1359  2009 Verlag Helvetica Chimica Acta AG, Zürich 1 ) For recent reviews, see [1].