PREPARATION AND CONFIGURATION OF RACEMIC AND OPTICALLY-ACTIVE ANALGESIC DIALKYLAMINOALKYLNAPHTHALENES

The alkylaminoalkylnaphthalene 3 shows interesting opioid-like analges ic properties, mu-selective ligand competition, and enkephalin hydroly zing enzyme inhibition. 3 possesses two chiral centers and can exist a s two racemic pairs and four diastereomers. Since the binding of opioi ds with the receptor is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (1R, 2R/1S, 2S)- and (1R, 2S/1S, 2R)-racemates and t he (1R, 2R)- and (1S, 2S)-enantiomers of the -hydroxynaphthyl)]-2-meth yl-3-dimethylaminopropane 3 is considered and the determination of abs olute configuration is described. The (1R,2R/1S,2S)-3 and (1R,2S/1S,2R )-3 racemates and the (1R,2R)-3 and (1S,2S)-3 enantiomers were prepare d by reaction of the racemic and optically active 1-dimethylamino-2-me thyl-pentan-3-one 2, respectively, with the lithiation product obtaine d from 2-bromo-6-tetrahydropyranyloxynaphthalene and acidic hydrolysis . The optical resolution of aminoketone 2 was carried out via fraction al crystallization of salts (+)- and (-)-dibenzoyltartrates. The confi guration of the optically active compounds was determined by X-ray ana lysis of a crystal of (+)-(1R, 2R)-3.HCl.H2O. Preliminary pharmacholog ical tests showed that (+)-(1R, 2R)-3 enantiomer is able to induce opi oid-like analgesia with a relative potency 2.5 times that of (1R, 2R/1 S, 2S)-3 and about 4 times that of morphine. (C) 1994 Wiley-Liss, Inc.