Study On The Synthesis Of5’-Methoxy-Laudanosine-Key Intermediate Of The Muscle Relaxant Mivacurium

Mivacurium is a new kind of excellent non-depolarizing muscle relaxants, which has the advantages of rapid onset and short duration of action, and no side effects and rapid postoperative recovery. It is the shortest kind of muscle relaxants on the duration of action ever discovered. At present, the domestic use of mivacurium all dependent on imports, no domestic manufacturers and reporting.There is only reports of the Mivacurium’s synthesis. Medicinal Chemistry workers focus more and more attention on this muscle relaxant for its excellent pharmacological activity and broad market prospects. The syntjesis research of mivacurium and its key intermediate have the great social and economic value.In this thesis, we investigate the synthesis of5’-methoxylaudanosine and important raw materials3,4,5-trimethoxyphenylacetic acid as key intermediate of mivacurium.First, we get the3,4,5-trimethoxybenzaldehyde by p-hydroxybenzaldehyde as a raw material, thus brominating through a novel green NaBr-H2SO4-H2O2bromide system, and then methoxy reacting by cuprous bromide catalyzed and sodium meth-oxide was refluxed in DMF, finally methylating with economic security dimethyl carbonate. The total yield of three-step reaction is68.9%, which the bromide method have not been reported.3,4,5-trimethoxybenzaldehyde as above was treated with CICH2COOCH3for Darzen condensation reaction, then following the rearrangement reaction and the oxidation reaction by the system NaClO2/H2O2to give3,4,5-trimethoxy phenylacetic. The total yield of three-step reaction is66.7%.The optimal condition of the Darzen condensation reaction is that3,4,5-trimethoxybenzaldehyde, CICH2COOCH3and the acid binding agent in a molar ratio of1:1.1:2, the haloacetic acid ester is methyl chloroacetate, the acid binding agent as K2CO3, and the solvent as DMF, the reaction temperature was25℃, the reaction time is18h, the reaction conversion rate was98%, more than99%selectivity. The synthesis rout of3,4,5-trimethoxyphenylacetic acid in the paper have not been reported. 3,4,5-Trimethoxyphenylacetic acid condensated with the industrialized compound3,4-dimethoxyphenylethylamine by the physical dehydration to get the amide, which was reacted by phosphorus oxychloride to form an isoquinoline ring, and then treated with methyl iodide in acetone on the methyl group, and finally reduced by KHB4to give the5’-methoxylaudanosine. the four-step reaction with a total yield of71.8%.This thesis complete the synthesis of5’-methoxylaudanosine by ten steps reaction over a total yield of33.5%, In the meaning time, some key reactions such as the bromination reaction, the methoxy reaction, Darzen condensation, the oxidation, cyclization and reduction reaction was discussed in detail including summing up the material ratio optimization and the choice of the reaction system and other important factors to determine the optimum reaction conditions. The process that we design has the reaction process is clear and easy to operate, easy to get cheap raw materials used reagent toxicity with high yield, etc. The paper was provided the preliminary theoretical basis for industrial production of mivacurium and its key intermediates.The paper obtained the key intermediate product and the target product of the5’-methoxylaudanosine were confirmed by IR,1H NMR,13C NMR and MS, are in line with the characteristics of the structure of the compounds.