Ghislandi V, Azzolina O, Collina S, Paroli E, Antonilli L, Giuseppetti G, Tadini C
Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy.
Chirality. 1994;6(5):389-99. doi: 10.1002/chir.530060506.
The alkylaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties, mu-selective ligand competition, and enkephalin hydrolyzing enzyme inhibition. 3 possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids 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 the (1R,2R)- and (1S,2S)-enantiomers of the 1-ethyl-1-hydroxy-1-[2-(6-hydroxynaphthyl)]-2-methyl-3- dimethylaminopropane 3 is considered and the determination of absolute 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 prepared by reaction of the racemic and optically active 1-dimethylamino-2-methylpentan-3-one 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxynaphthalene and acidic hydrolysis. The optical resolution of aminoketone 2 was carried out via fractional crystallization of salts (+)- and (-)-dibenzoyltartrates. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (+)-(1R,2R)-3.HCl.H2O. Preliminary pharmacological tests showed that (+)-(1R,2R)-3 enantiomer is able to induce opioid-like analgesia with a relative potency 2.5 times that of (1R,2R/1S,2S)-3 and about 4 times that of morphine.
烷基氨基烷基萘3具有有趣的类阿片样镇痛特性、μ-选择性配体竞争以及脑啡肽水解酶抑制作用。3具有两个手性中心，可作为两个外消旋对和四个非对映异构体存在。由于阿片类药物与受体的结合具有立体选择性，拥有这两个外消旋对以及四个非对映异构体很重要。本文考虑了1-乙基-1-羟基-1-[2-(6-羟基萘基)]-2-甲基-3-二甲基氨基丙烷3的(1R,2R/1S,2S)-和(1R,2S/1S,2R)-外消旋体以及(1R,2R)-和(1S,2S)-对映体的合成，并描述了绝对构型的确定。(1R,2R/1S,2S)-3和(1R,2S/1S,2R)-3外消旋体以及(1R,2R)-3和(1S,2S)-3对映体分别通过外消旋和旋光活性的1-二甲基氨基-2-甲基戊-3-酮2与由2-溴-6-四氢吡喃氧基萘得到的锂化产物反应并经酸性水解制备。氨基酮2的拆分通过(+)-和(-)-二苯甲酰酒石酸盐的分步结晶进行。通过对(+)-(1R,2R)-3·HCl·H₂O晶体的X射线分析确定了旋光活性化合物的构型。初步药理试验表明，(+)-(1R,2R)-3对映体能够诱导类阿片样镇痛，相对效力是(1R,2R/1S,2S)-3的2.5倍，约为吗啡的4倍。
