Investigation of the synthesis and analgesic activity of 1‐substituted 4‐(propananilido)perhydroazepines

Methods are explored to enhance the efficiency and versatility of the synthesis of the 1-substituted 4-(propananilido)perhydroazepine analgesics. The modified synthesis begins with ring expansion of 1-carbethoxy-4-piperidinone 3 with ethyl diazoacetate and boron trifluoride to yield 1,5-biscarbethoxyperhydroazepin-4-one 4. Selective hydrolysis of 4 followed by decarboxylation provides 1-carbethoxyperhydroazepin-4-one 6. Reductive amination of 6 with aniline affords the 4-anilino intermediate 7 which is treated with propionic anhydride to give 1-carbethoxy-4-(propananilido)perhydroazepine 18. Selective cleavage of the 1-carbethoxy group of 18 was accomplished with trimethylsilyliodide to yield the versatile intermediate 4-(propananilido)-perhydroazepine 19. Treatment of 19 with styrene oxide afforded the 1-[2-(1-hydroxy-1-phenyl)ethyl] derivative 1c which, in the tail-flick assay, displays greater analgesic potential than previously reported members of this series.