Synthesis of oxazolo-annulated 3-benzazepines designed by merging two negative allosteric NMDA receptor modulators

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 K2CO3-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.