Study On The Synthesis Of Cisatracurium Besilate

Cisatracurium besilate,which is currently a clinically ideal medium-aging non-depolarizing muscle relaxant,has the advantages of fast onset and strong potent without release of histamine and toxicity of metabolites.Cisatracurium besilate has been gradually the mainstream of muscle relaxants and widely used at home and abroad.In the present article,the synthetic technology of cisatracurium besilate was optimized based on the reported method for synthesizing in literature.1,5-Pentanediol diacrylate was synthesized by using 1,5-pentanediol and methyl acrylate as the starting materials through transesterification.The key intermediate 5-[3-[(1R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1H-iso-quinolin-2-yl]propanoyloxy]pentyl-3-[(1R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-di-meth oxy-3,4-dihydro-1H-isoquinolin-2-yl]propanoate was obtained by Michael addition from R-tetrahydropapaverine base and 1,5-pentamethylene diacrylate.This intermediate was methylated with methyl benzenesulfonate to form a mixture of atracurium besylate isomers,which were purified by column chromatography to afford the final product cisatracurium besilate.A series of factors such as the feed ratio,reaction temperature,reaction time,and the dose of catalyst,amount of solvent and post-treatment method were optimized to determine the optimal reaction condition for each step of the reaction.Appropriate amount of p-benzoquinone enzoquinone was used as a polymerization inhibitor in the transesterification,as a result,the post-treatment temperature and the equipment requirement was reduced.In Michael addition,the appropriate feed ratio and catalyst amount were used to avoid the generation of impurities.Water was used instead of acetic anhydride to remove the unreacted raw material R-tetrahydropapaverine,which was then recovered by extracted from the aqueous phase with dichloromethane.Five impurities were separated during the reaction.The structure of cisatracurium besilate,intermediates and impurities were characterized by ~1HNMR,IR,and LC-MS,respectively.The high performance liquid chromatography characterization method was established for the product of Michael addition reaction.The established chromatography method provided a feasible approach for the reaction monitoring and intermediate quality control.The quality of synthesized cisatracurium besilate met the requirements of the Chinese Pharmacopoeia(2015 Edition)by HPLC.The optimized synthetic process conditions of cisatracurium besilate were mild and easy to operate,which is expected to be used in the industrial production.The total yield of cisatracurium besilate was of 36.65%(based on 1,5-pentanediol).