Gustavson L M, Nelson W L
Dept. of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Drug Metab Dispos. 1988 Mar-Apr;16(2):217-21.
Regioisomeric monomethyl ethers of the 3,4-catechol of propranolol (1) and its 3-aryloxypropane-1,2-diol (glycol) metabolite were prepared to prove the structures of these putative products of oxidative metabolism. The ring regioisomer 4-methoxy-3-hydroxypropranolol (3) was prepared from 1-acetoxy-3-acetyl-4-methoxynaphthalene (8). Baeyer-Villiger oxidation was the key step in converting the 3-acetyl functionality to the desired 3-naphthol. The ring regioisomer 4-hydroxy-3-methoxypropranolol (4) was prepared from 3-methoxy-1,4-dihydroxynaphthalene (13) by selective 1-O-acylation with trimethylacetyl chloride. 4-O-Benzylation, followed by hydrolysis, and side chain elaboration afforded the 4-O-benzyl ether of 4. Similar methods afforded glycols 5 and 6, with the side chain obtained by osmium tetroxide oxidation of an O-allyl group. GC/MS analysis using the trifluoroacetyl derivatives of these known standards showed both 3 and 4 were metabolites of 1 in the rat. From a single dose study in man, 4 was identified as a minor urinary metabolite, and both regioisomeric glycol metabolites 5 and 6 were observed. In addition, another regioisomeric hydroxymethoxyglycol metabolite was found.
制备了普萘洛尔（1）的3,4-邻苯二酚的区域异构体单甲醚及其3-芳氧基丙烷-1,2-二醇（二醇）代谢物，以证实这些推定的氧化代谢产物的结构。环区域异构体4-甲氧基-3-羟基普萘洛尔（3）由1-乙酰氧基-3-乙酰基-4-甲氧基萘（8）制备。拜耳-维利格氧化是将3-乙酰基官能团转化为所需的3-萘酚的关键步骤。环区域异构体4-羟基-3-甲氧基普萘洛尔（4）由3-甲氧基-1,4-二羟基萘（13）通过用三甲基乙酰氯进行选择性1-O-酰化制备。4-O-苄基化，随后水解，并进行侧链修饰，得到4的4-O-苄基醚。类似的方法得到二醇5和6，其侧链通过O-烯丙基的四氧化锇氧化获得。使用这些已知标准品的三氟乙酰衍生物进行的GC/MS分析表明，3和4都是大鼠体内1的代谢物。在人体的单剂量研究中，4被鉴定为一种次要的尿液代谢物，并且观察到了两种区域异构体二醇代谢物5和6。此外，还发现了另一种区域异构体羟基甲氧基二醇代谢物。
