Study On The Synthesis Of New Muscle Relaxant Antagonists

A series of per-6-substituted cyclodextrin derivatives as a new amino-steroidal muscle relaxant antagonists,were widely used in drug-induced neuromuscular reversal of anesthesia,these drugs are safe,fast and effective antagonism of rocuronium with other steroidal nondepolarizing muscle relaxant muscle relaxant effect.This work is aimed at optimizing and improving the synthesis route of the product. After the redesign of the first derivative use γ-cyclodextrin as starting materials,through bromination and nucleophilic substitution reaction obtained the product 6-perdeoxy-6-per(2-carboxy-ethyl)thio-γ-cyclodextrin sodium salt,and the total yield is 70.4%.And the redesign of the second derivative also use γ-cyclodextrin as starting materials,through bromination,thiosulfate reaction and nucleophilic substitution reaction obtained the product 6-perdeoxy-6-per[[2-(2-carboxybenzoyl)amino]ethyl]thio-γ-cyclodextrin sodium salt, and the total yield is 39.8%. Compared with the original synthesis route,this improved synthesis route is simple,reduce production costs,improve yields.The structure of the product was characterized by IR,1H-NMR,MS and MALDI-TOF-MS.For the first derivative 6-perdeoxy-6-per(2-carboxy-ethyl)thio-γ-cyclodextrin sodium salt,the first step,Vilsmeier reagent is first prepared, in the reaction with γ-cyclodextrin to give 6-perdeoxy-6-perbromo-y-cyclodextrin. In this step, two methods were used, the first use bromine, triphenylphosphine and DMF to get Vilsmeier reagent, this method is complicated operation,complicated post-treatment and low yields; the second is prepared by N- Bromosuccinimide, triphenylphosphine and DMF, the method is simple and get a higher yield. The second approach made a series of single-factor study, mole ratio of reactants, reaction time and reaction temperature on the experiment to determine the optimal reaction conditions.The second step, it is a typical nucleophilic substitution reaction.First sodium hydride and 3-mercaptopropionic acid reaction to forming a strong nucleophile.The improevd synthesis process is mild reaction conditions, high yields, environmental pollution and product purity. The best reaction condition was generated after the attempt of a variety of the ratios.For the second derivative 6-perdeoxy-6-per[[2-(2-carboxybenzoyl)amino]ethyl]thio-γ-cyclodextrin sodium salt, the first step as the step of the first derivative,the secong step, its a nucleophilic substitution reaction. And in this step, the study of a single factor and reaction temperature, reaction time, to determine the optimal reaction conditions and after the attempt of a variety of the ratios, the best reaction condition was generated.The third step was using O-Phthalimide and 1,2-Dibromoethane to get the raw material. The step four was the reaction between 6-perdeoxy-6-perthiol-y-cyclodextrin and N-(2-Bromoethyl)phthalimide. The best reaction condition was generated after the attempt of a variety of the ratios.