Study On The Chlorination Process Of R-(P-Methoxybenzyl)-Octahydroisoquinline In The Microreactor

The microreactors are of great significance for the development of environmentally friendly processes and the realization of green chemistry.In this paper,the chlorination process of R-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline was studied using microreactors.The continuous flow process of racemization was developed for the recovery of dextromethorphan chiral intermediate.The sodium hypochlorite which is cheap,easy to use,and safe was chosen as the chlorinating agent by analyzing the characteristics of raw materials,products,and the chlorinating agents such as sodium hypochlorite,N-chlorosuccinimide,and t-butyl hypochlorite.By analyzing the reaction mechanism,the chlorination reaction is a rapid exothermic reaction,and highly active N-chloramine is generated in the process.The possible intermediates of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline,R-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline,and 1-(4-methoxybenzyl)-5,6,7,8-tetrahydroisoquinoline in the chlorinating process were synthesized as standard sample and the analysis method was developed.The reaction kinetics of chlorination of R-(p-methoxybenzyl)-octahydroisoquinoline with sodium hypochlorite was studied.The kinetic equation of chlorination reaction was obtained by determining the concentrations of reactants and product in different time at a given temperature.The activation energy E_a was obtained by Arrhenius equation,which is56.62 kJ/mol.The fluid flow mechanics of the microreactor were evaluated by the images analysis of the mixing of the two liquid phases in the microreactor,and by kinetic analysis of the chlorination reaction in the temperature range of 0~°C to 60~°C.When the flow rate of the feed reached 100 mL/min,the theoretical plug flow was achieved in the microreactor by validation of reaction kinetics.The R-(p-methoxybenzyl)-octahydroisoquinoline chlorination process in the microreactor was investigated under the condition of theoretical plus flow reactor.The effects of substrate molar ratio,flow rates ratio,solvent usage and temperature on reaction yield of the chlorination process in the microreactor were studied.The optimal operating conditions for the chlorination process in the microreactor are determined as follows:the optimal flow ratio of the organic phase to the aqueous phase is4:1,the molar ratio of R-(p-methoxybenzyl)-octahydroisoquinoline to sodium hypochlorite is 1:1,and the optimal reaction temperature is 40°C.Under the optimum operating conditions,the racemic recycled process flow of by-product R-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline from chiral resolution of dextromethorphan intermediate was designed and the continuous production was studied.The results showed that compared with batch process,the yield of chlorination reaction increased from 85%to96%and the percentage of aromatization compound decreased from 10%to 3.2%by using the series process of microreactor and continuous stirred tank reactor.In this thesis,under the guidance of reaction kinetics and the optimization of flow and reaction conditions in the microreactor,R-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline chlorination reaction was carried out in micro reactor,a continuous recycled method for racemic intermediates in dextromethorphan was achieved.The chlorination process can be continuously produced,safe and simple to operate,and is of great significance for environmentally friendly chemical production.