PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .9. SYNTHESIS OF (+--)-(3-ALPHA,6A-ALPHA,11A-BETA)-1,3,4,5,6,11A-HEXAHYDRO-2-METHYL-2H-3,6A-METHANOBENZOFURO[2,3-CIS]AZOCIN-10-OL, AN OXIDE-BRIDGED 5-(META-HYDROXYPHENYL)MORPHAN
PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .9. SYNTHESIS OF (+--)-(3-ALPHA,6A-ALPHA,11A-BETA)-1,3,4,5,6,11A-HEXAHYDRO-2-METHYL-2H-3,6A-METHANOBENZOFURO[2,3-CIS]AZOCIN-10-OL, AN OXIDE-BRIDGED 5-(META-HYDROXYPHENYL)MORPHAN
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DOI：
10.1021/jm00155a026
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发表时间：
1986-05-01
影响因子：
7.3
通讯作者：
SILVERTON, JV
中科院分区：
文献类型：
--
作者：
BURKE, TR;JACOBSON, AE;SILVERTON, JV
消旋体（3. α,6 . α,11 . α）的合成描述了-1,3,4,5,6,11 - a-六氢-2-甲基- 2h -3,6 - a-甲烷苯并呋喃[2,3-c]偶氮辛-10-醇（2d）。该方法利用酸催化的烯胺5闭合环生成不饱和的苯基吗啡6。将6转化为氧化物桥接的2d是通过多步骤的方式完成的，利用溴原子的引入，然后是酚甲基醚的o -去甲基化和碱催化的溴的分子内苯氧化合物置换。化合物(+ -)。-2d是有效的5-（间羟基苯基）吗啡类阿片类镇痛药的氧化物桥接衍生物1。与具有自由旋转苯基的5-（间羟基苯基）变体不同，2d的苯基环构象限制为49度角。相对于2d的原子1,3,11a和12。（.+-.）的低结合-2d到大鼠脑匀浆受体制剂[IC50 = 1000 nM]可能表明苯基角为49度。不适合与阿片受体结合。
The synthesis of racemic (3.alpha.,6a.alpha.,11a.beta.)-1,3,4,5,6,11a-hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (2d) is described. The route used acid-catalyzed ring closure of enamine 5 to yield the unsaturated phenylmorphan 6. Conversion of 6 to oxide-bridged 2d was accomplished in a multistep fashion that utilized the introduction of a bromine atom, followed by O-demethylation of the phenolic methyl ethers and base-catalyzed intramolecular phenoxide displacement of the bromine. Compound (.+-.)-2d represents an oxide-bridged derivative of the potent 5-(m-hydroxyphenyl)morphan class of opioid analgesics 1. Unlike the 5-(m-hydroxyphenyl)morphans that have a freely rotating phenyl group, 2d has the phenyl ring conformationally restricted at an angle of 49.degree. relative to atoms 1, 3, 11a, and 12 of 2d. The low binding of (.+-.)-2d to rat brain homogenate receptor preparations [IC50 = 1000 nM] may indicate that the phenyl angle of 49.degree. is not suitable for binding to opioid receptors.