Synthesis Of (-)-Galanthamine

As a cholinesterase inhibitor,(-)-galantamine was originally used to treat myasthenia gravis,sequelae of polio,and intestinal paralysis.In recent years,some research shows that it can also be used to treat Alzheimer’s disease with obvious effects.The traditional production method of galantamine is the separation and extraction from lycoris radiate but with low yield and cumbersome operation,and the resource is scarce.At present,the chemical synthesis of galantamine has been dustrialized,but with low yield,harsh conditions,high cost,and not eco-friendlly.Therefore,it is necessary to develop a highly efficient and low-pollution synthesis process.In this paper,the optimization of the conditions for the synthesis of galantamine intermediates was studied.The bioenzyme preparation method of(-)-galantamine has been explored,bio-catalysts such as lipase,whole microorganisms,and carbonyl reductase were used to biosynthesize(±)-galantamine and its key intermediate Navigine.The target molecular(-)-galantamine was successfully obtained.The chemical-enzymatic synthetic route includes 8-step chemical reactions and 1-step enzymatic esterification or enzymatic reduction.Using verataldehyde as raw material,bromination to obtain 2-bromo-4,5-dimethoxybenzaldehyde,and then demethylation to give 6-bromoisovanillin,then reductive condensation and N-methylated to give N-(2-bromo-5-hydroxy-4-methoxybenzyl)-4-hydroxyphenethyl-methylamine,oxidatively coupled to cyclization to give racemic Brnavifin.Racemic Navigine was obtianeed by debrominated of Brnavifin,followed by enzymatic resolution to give(-)-navidudine in 15.0% yield,which was 5% higher than that reported in the literature.Lithium aluminum hydride reduction of(-)-navidudine to give racemic galantamine,the(-)-galantamine could be obtained by enzymatic esterification.Alternatively,using the whole microorganism or carbonyl reductase to catalyze the conversion of the carbonyl to hydroxy in the key intermediate(-)-Navildine,to yield(-)-galantamine.More importantly,the enzymatic esterification of racemic galantamine by enzymatic resolution and the conversion of carbonyl by biological methods have not been reported yet.Although the yield is not increased,the operating conditions are simple,has the value of further optimization and improvement.Besides,the paper provides a new method for synthesis of(-)-galantamine.