Leland D L, Kotick M P
J Med Chem. 1981 Jun;24(6):717-21. doi: 10.1021/jm00138a015.
Treatment of dihydrocodeinone (1a) or the 8 beta-methyl (1b) or 8 beta-ethyl (1c) analogues with formaldehyde-Ca(OH)2 in aqueous dioxane gave the corresponding 7,7-bis(hydroxymethyl)-6 beta-ols 2a-c. Ditosylation of 2, followed by LiEt3BH reduction, gave either the 7,7-dimethyl-6 beta-ol (6a) or 7 alpha-methyl-6 beta, 7 beta-oxetane compounds (5b,c). Compounds 5b and 5c were cleaved to 6b or 6c using LiAlH4-AlCl3. The configuration of the C6-alcohol group of 6a was confirmed by an oxidation-reduction sequence which gave the 7,7-dimethyl-5 alpha-ol 8a. Oxidation of 6 gave the C6-ketones 7a-c, which were converted to N-(cycloalkylmethyl) derivatives 11 and 12 and their corresponding 3-hydroxy compounds 14 and 15. The 3-methoxy-7,7-dimethyl-6-ones 7 were as active as dihydrocodeinone in agonist assays. One compound of this series, N-(cyclopropylmethyl)-7,7-dimethyldihydronorcodeinone (11a), was a potent mixed agonist-narcotic antagonist.
将二氢可待因酮（1a）或其8β-甲基（1b）或8β-乙基（1c）类似物与甲醛 - 氢氧化钙在二氧六环水溶液中反应，得到相应的7,7 - 双（羟甲基）-6β-醇2a - c。2经二对甲苯磺酰化，然后用三乙基硼氢化锂还原，得到7,7 - 二甲基-6β-醇（6a）或7α-甲基-6β,7β-氧杂环丁烷化合物（5b，c）。使用氢化铝锂 - 氯化铝将化合物5b和5c裂解为6b或6c。通过氧化 - 还原序列确认了6a的C6 - 醇基团的构型，该序列得到了7,7 - 二甲基-5α-醇8a。6的氧化得到C6 - 酮7a - c，其被转化为N - （环烷基甲基）衍生物11和12以及它们相应的3 - 羟基化合物14和15。在激动剂测定中，3 - 甲氧基-7,7 - 二甲基-6 - 酮7与二氢可待因酮活性相当。该系列中的一种化合物，N - （环丙基甲基）-7,7 - 二甲基二氢去甲可待因酮（11a），是一种有效的混合激动剂 - 麻醉拮抗剂。
