Vecuronium bromide and its advanced intermediates: A crystallographic and spectroscopic study

Vecuronium bromide (Piperidinium, 1-[(2 beta,3 alpha,5 alpha,16 beta,17 beta)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron (R)) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3 beta-hydroxy-5 alpha-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the H-1, C-13, and N-15 NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2 beta,16 beta-bispiperidino-5 alpha-androstane-3 alpha,17 beta-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation.