Study On The Synthetic Technics Of Vecuronium Bromide Intermediates And Rocuronium Bromide

Rocuronium Bromide and Vecuronium Bromide are new kinds of monoquaternary aminosteroidal muscle relaxants (also named Neuromuscular Blocking Agents),which are clinically used as anesthesia adjuvants in the operation therapy, to enable endotracheal intubation and to facilitate mechanical ventilation. They are current muscle relaxants known for their noncumulative, nondepolarising neuromuscular action with rapid onset and recovery, no cardiac vagolytic effects and no histamine release. Rocuronium Bromide is one of the most rapid onset nondepolarising neuromuscular blocking agents and Vecuronium Bromide is one of the most safety neuromuxcular blocking agent among the stupefacient. So they are used worldwidely.This thesis mainly study on the synthetic technics of Rocuronium Bromide and Vecuronium Bromide. The synthetic methods of the two key intermediates 5α-androst-2-en-17-one and 2β-(4-morpholine)-16β-(1-pyrrolidinyl)- 3α,17β-dihydroxy-5α-androstane were properly modified, and the synthetic conditions of Rocuronium Bromide and Vecuronium Bromide were optimized based on literatures.Using epiandrosterone as starting material, 5α-androst-2-en-17-one was synthesized via tosylation and elimination with a good yield up to 78%,(literature value 39% ). This new synthetic route is more shortening the reaction time, lowering the cost of the raction and more easy treating the process and quality control than the references.The synthetic conditions of 2β,16β-bis-piperidin-3α,17β-dihydroxy-5α- androstane was optimized, and the yield was improved to 60% with recrystallization, after the ring opening reaction of 2α,3α-epoxy-17-oxo-16β-pyrrolidine-5α- androstane by aqueous morporline and the reduction of the ketone with sodium borohydride. Finally, Rocuronium Bromide was synthesized. Acetylation of the diol gave a mixture of the 17-monoacetyloxy and the 3,17-diacetyloxy derivatives from which the 17-monoacetate was sepatated by crystallization. Treatment of the monoacetyloxy compound with allyl bormide afforded Rocuronium Bromide. In this reaction, acetonitrile was used as solvent, then recrystallized to give the pure product without column chromatography purification. Consequently, the yield was improved to 88%,(literature value 68% ). The total yield of Rocuronium Bromide is 13.4%. [α]D=+29.5 (c=1 HCl),The chemical structure of Rocuronium bromide and its intermediate were confirmed by 1H NMR and MS. The Purity of Rocuronium Bromide was up to 99.08% and could meet to the standard of European Pharmacopoeia 5.4.In addition, the preparasion of intermediates of Vecuronium Bromide, 2β,16β-bis-piperidin-3α,17β-dihydroxy-5α-androstane, was also modified based on literature with an improved yield of 16%, (literature value 6.8% ). The intermediate then methylation with bromomethane could afford vecuronium bromide, now this step is in progress. The chemical structure of its all intermediates were confirmed by 1H NMR and MS.