Study On The Synthetic Technique Of Relaxing Muscle Agent Pipecurium Bromide

Pipecuronium bromide is a long-acting nondepolarizing neuromuscularblocking agent, which was developed by Gedeon Richter Ltd. of Hungary. As aadjuvant in anaesthetization, it has come into the market in Brazil, Russia, Hongkongsuccessively. Its processes of synthesis has not been reported at home, and there areonly few literatures overseas. At present, the demand of pipecuronium bromide athome mostly depend on importation. So developing a new process which can adaptto plant-scale production has a great deal of profit.According to references, we changed epi-androsterone by steps of tosylationand elimination into 5α-androst-2-ene-17-one, with 70.5ï¼…overall yield. Wecontrasted the two different processes for the synthesis of2β,16β-bis-(4-methy-1-piperazinyl)-3α-hydroxy-5α-androstane-17-one. As a result,the two processes have a similar result; however, in the second route, synthesis of17β-acetoxy-5α-androsta-2,16-diene has a lower yield, and crystallization time of theproduct can not be hold easily. So the first method is preferred. After substitution andepoxidation on the compound (2) in turn, the compound (12) reacted withN-methyl-piperazine in atmosphere without N₂, in 51.7ï¼…yield. In followingreduction, hygroscopic NaBH₄ was replaced with KBH₄ that is used widely inplant-scale. Methanol was used as solvent, substituting THF that is expensive,working process was simplified in 88.2ï¼…yield (literature: 82ï¼…yield). Duringesterification, CH₂Cl₂ was usede for the solvent, and the quantity of acetic anhydridewas decreased greatly. In post treatment, we distilled off the solvent and aceticanhydride, the residue was alkalized, and then extracted in order to save the quantity of Na₂CO₃ and time. obtained oily liquid was not necessary further dealed withhexane, resulting in acceptable purity and a higher yield(83.7ï¼…). In successioncarded out methylation with methanesulfonate, then substitution with LiBr, thuspipecuronium bromide was achieved, with a overall 12ï¼…yield. The end product andsome intermediates were confirmed by means of ¹HNMR.The thesis emphasize the discussion on purification of the end product andintermediates. Most experiments showed post treatment of the compound (7) relatedto formation of impurities in the end product. This will make the production ofpipecuronium bromide possible at home.The process that we reported has some merits, such as reaction conditions areall mild, the post treatments are simple and adapt to plant-scale production...