A novel and facile preparation of bremazocine enantiomers through optically pure N-norbremazocines.
In order to provide ready access to multigram quantities of the optically pure bremazocines [(-)- and (+)-9,9-dimethyl-5-ethyl-2-hydroxy-2-(1-hydroxy-cyclopropylmethyl)-6,7-benzomorphan)], we have developed an improved non-chromatographic synthesis, and determined the optical purity of their N-nor precursors using a rapid and relatively simple 1H NMR method based on diastereomeric derivatization with optically pure 1-phenylethylisocyanate. This method of determining optical purity should be readily amenable to similar systems containing phenolic amino functionalities. Finally, a greatly simplified methodology for introduction of the N-(1-hydroxycyclopropylmethyl) substituent in bremazocine is described. The improved synthetic method-the overall yield was increased about 3-fold-combined with the practical methodology to determine optical purity will considerably facilitate the employment of these enantiomers as pharmacological tools for examination of the kappa-opioid receptor system, as well as their evaluation as drug abuse treatment agents. This synthesis will also enable the study of these enantiomers for other, non-classical applications (e.g., treatment agents for HIV).
Greiner
Elisabeth
E
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, 8 Center Drive, MSC 0815, Bethesda, MD 20892-0815, USA.
Folk
John E
JE
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D001575:Benzomorphans / Q000032:analysis* / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D009904:Optical Rotation; D013237:Stereoisomerism
D001575:Benzomorphans; C027248:bremazocine