Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Münster, Germany.
GRK 2515, Chemical Biology of Ion Channels (Chembion), Westfälische Wilhelms-Universität Münster, Münster, Germany.
Arch Pharm (Weinheim). 2022 Jun;355(6):e2200020. doi: 10.1002/ardp.202200020. Epub 2022 Feb 27.
To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3-benzazepone moiety of WMS-1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5-(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel-Crafts acylation of acid 12a containing the N-tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron-withdrawing triflyl group resulted in the desired 3-benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K CO -induced elimination of trifluoromethanesulfinate. In a one-pot three-step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.
为了提高ifenprodil（1）的代谢稳定性和受体选择性，将besonprodil（2）的苯并恶唑酮部分和 WMS-1410（3）的 3-苯并氮杂环酮部分合并，得到了苯并恶唑并苯并氮杂环酮类化合物 4。以 4-（2-羟乙基）苯酚（8）为起始原料，经过四步反应制备了代表第一个关键中间体的 5-（羟乙基）苯并恶唑酮 7。伯醇 7 与 N-磺酰化甘氨酸酯的 Mitsunobu 反应建立了必要的侧链。含有 N-对甲苯磺酰基保护基的酸 12a 的分子内 Friedel-Crafts 酰化反应，经脱羰反应，仅得到三环四氢异喹啉 14。用吸电子能力更强的三氟甲磺酸酯基保护氨基，得到所需的 3-苯并氮杂环酮 15，而不会形成类似的异喹啉。用 K CO 诱导脱除三氟甲磺酸盐，除去三氟甲磺酸酯保护基。在一锅三步法中，得到了各种苯并恶唑并苯并氮杂环酮二酮 15，将其还原得到所需的仲醇 18。
