Kirk K L, Cantacuzene D, Nimitkitpaisan Y, McCulloh D, Padgett W L, Daly J W, Creveling C R
J Med Chem. 1979 Dec;22(12):1493-7. doi: 10.1021/jm00198a012.
2-Fluoro-, 5-fluoro- and 6-fluorodimethoxybenzaldehydes were prepared by photochemical decomposition of the corresponding diazonium fluoroborates. The aldehydes were converted to the cyanohydrin trimethylsilyl ethers, which, in turn, were reduced to the dimethoxyphenethanolamines. Boron tribromide demethylation afforded the racemic ring-fluorinated norepinephrines. An alternate route, using the dibenzyloxyfluoroaldehyde, was also used to prepare 6-fluoronorepinephrine. The fluorine substituent markedly increases the phenolic acidities of these analogues. The biological properties conferred upon norepinephrine by the fluorine substituents in peripheral and central adrenergically responsive systems clearly demonstrate that 2-fluoronorepinephrine is a nearly a pure beta-adrenergic agonist, while 6-fluoronorepinephrine is an alpha-adrenergic agonist. 5-Fluoronorepinephrine retains both beta- and alpha-adrenergic agonist properties. Receptor-binding studies with specific radiolabeled ligands indicate that the specificity conferred by the site of fluorine substituents results from a change in the affinity of these analogues for the alpha- and beta-adrenergic receptors.
2-氟、5-氟和6-氟二甲氧基苯甲醛是通过相应氟硼酸重氮盐的光化学分解制备的。醛被转化为氰醇三甲基硅醚，后者又被还原为二甲氧基苯乙醇胺。三溴化硼脱甲基得到外消旋环氟化去甲肾上腺素。还采用了一条使用二苄氧基氟醛的替代路线来制备6-氟去甲肾上腺素。氟取代基显著增加了这些类似物的酚酸性。氟取代基在外周和中枢肾上腺素能反应系统中赋予去甲肾上腺素的生物学特性清楚地表明，2-氟去甲肾上腺素几乎是一种纯β-肾上腺素能激动剂，而6-氟去甲肾上腺素是一种α-肾上腺素能激动剂。5-氟去甲肾上腺素同时保留β-和α-肾上腺素能激动剂特性。用特定放射性标记配体进行的受体结合研究表明，氟取代位点赋予的特异性是由于这些类似物对α-和β-肾上腺素能受体亲和力的变化所致。
