Study On The Synthesis Process Of Amantadine Quaternary Ammoniun Base

Amantadine quaternary ammonium salts and quaternary ammonium bases play an important role in the fields of industry and medicine,due to the specific cationic surface activity and colloidal chemical properties of quaternary ammonium hydroxide.Then,SSZ-13 molecular sieve is synthesized by using it as a template,which exhibits excellent catalytic performance in selective catalytic reduction,adsorption separation,and MTH reactions.At present,the traditional method of preparing amantadine quaternary ammonium salt is that 1-amantadine as a raw material,reduced by formic acid formaldehyde system,and then methylated with dimethyl sulfate（DMS）.However,the reaction time of this process is too long,and DMS is highly toxic,corrosive and carcinogenic,and there is too much waste water in the production process,which has a negative impact on production and life.Therefore,a green method for the synthesis of amantadine quaternary ammonium base was developed in this paper.First,using 1-adamantylamine as a raw material and dimethyl carbonate（DMC）as a methylating reagent,the intermediate N,N,N-trimethyl-1-adamantylmethylammonium carbonate was synthesized.Then,the intermediate was hydrolyzed and reacted with calcium hydroxide to obtain the final product N,N,N-trimethyl-1-adamantylammonium hydroxide.The structures of quaternary ammonium salts and quaternary ammonium bases were characterized by ¹H-NMR and ¹³C-NMR.In the synthesis of amantadine quaternary ammonium salt,through single factor experiment and orthogonal experiment,the optimum process conditions were determined as follows:reaction temperature 140C,catalyst dosage m（DMF）:m（1-amantadine）=0.25,reaction time 5h and n（1-amantadine）:n（DMC）=1:8.Under these conditions,the yield of the quaternary ammonium salt could reach 97.3%.Through the separation and purification of the by-products,the structure of the by-products was determined to be the result of DMC methoxycarbonylation.And through single-factor experiments,it is concluded that when DMF was used as the catalyst,and the dosage is25%of the mass of 1-amantadine,and the reaction temperature was 140℃,the by-products had the least influence on the methylation reaction.In the synthesis of amantadine quaternary ammonium base,the best hydrolysis condition of amantadine methyl ammonium carbonate obtained by single factor experiment was that m（water）:m（raw material）=3:1,reaction temperature 50℃,reaction time 2.5 h.Under this process condition,the hydrolysis conversion rate reached100%.The optimal reaction conditions for the synthesis of amantadine quaternary ammonium base obtained by single factor experiment were that n（adamantyl ammonium bicarbonate）:n（calcium hydroxide）=1:1.2,the reaction temperature was70℃,and the reaction time was 2 h.The concentration of amantadine quaternary ammonium base obtained by this process was determined by acid-base titration to be about 20%,and the concentration of residual calcium ions in the product was determined by atomic absorption method to be less than 5 mg/L,which have met market requirements.In summary,this process uses DMC as the methylation reagent to develop a green and environmentally friendly process route for the synthesis of amantadine quaternary ammonium base,which has certain application prospects.