The Researches On Synthesis Process Of Atomoxetine Hydrochloride

Atomoxetine hydrochloride is the first non-psychoactive drug used in the treatment of attention deficit hyperactivity disorder（ADHD）,which has the advantages of remarkable efficacy,good safety and non-addiction.At present,Atomoxetine hydrochloride has become the first-line therapy recommended in the guidelines for the treatment and prevention of ADHD,so it is of great significance to study the synthesis process of Atomoxetine hydrochloride.This paper based on the analysis and study of several synthetic route,and through a large number of experimental verification,identified a few steps,low cost,easy to operate and suitable for industrialization route:First of all,N-methylbenzylamine was synthesized from benzyl chloride and methylamine solution,and the corresponding hydrochloride was obtained by"one-pot"Mannich reaction method.Then,Atomoxetine hydrochloride was obtained through carbonyl reduction,catalytic hydrodebenzylation,etherification,and chiral separation into salt.A series of optimized synthesis conditions were analyzed.The main contents are as follows:（1）N-methylbenzylamine was used as the raw material of Mannich reaction,N-methylbenzylamine was synthesized by benzyl chloride and methylamine,and then the excess methylamine solution was recovered by simple vacuum distillation,and then the Mannich reaction was carried out directly.There was no need to separate N-methylbenzylamine,and the finished product TM-1 was obtained by filtration.The yield and purity were significantly increased,with the yield of 84.5%and purity of 99.3%.At the same time,the Mannich reaction involving methylamine was studied.By comparison,N-methylbenzylamine was selected as the simple operation and low cost,which improved the feasibility of the process and avoided the cumbersome post-treatment steps.（2）Na BH₄was selected as the reducing agent in the reaction of reducing TM-2,which has the advantages of low price,good reducibility,mild reaction conditions,complete reaction and simple post-treatment,and the yield and purity of the product were 84.3%and 95.1%.（3）TM-3 was prepared by hydrogenation catalytic debenzyl.High selectivity and environmental friendliness,the yield reached 84.7%.Although the use of N-methylbenzylamine as the raw material for the Mannich reaction will increase the step of removal benzyl,the product obtained by the two steps is of good purity,with a yield of more than 80%.The total yield and purity is also higher than that of methylamine,so it is better than the use of methylamine reaction.（4）In the etherification reaction,o-fluorotoluene was selected as the etherification reagent,which simplified the synthesis of TM-4,and the operation was simple.The product can be directly salted with oxalic acid with purity up to 99.4%.（5）The effect of four tartaric acid derivatives,S-mandelic acid and L-tartaric acid were compared.It was found that L-dibenzoyl tartaric acid had the best effect on the resolution of TM-4,and the yield of toloxetine hydrochloride was 40.4%.In addition,Atomoxetine hydrochloride is one of the sitine psychotropic drugs,and we hope that the synthesis process route of Atomoxetine hydrochloride can be applied to the synthesis of the key intermediate of Duloxetine hydrochloride with similar structure,so as to solve the synthesis problem of sitine drugs.Therefore,on the basis of the synthesis process of Atomoxetine hydrochloride,we expanded the synthesis of Duloxetine hydrochloride key intermediates,using thiophene as raw material,through acylation,Mannich reaction,reduction and debenzylation to obtain the key intermediate 3-（N-methyl）-1-（2-thiophenyl）-1-propanol,and the experimental study of its process.The purity of3-（N-methyl）-1-（2-thiophenyl）-1-propanol was 96.3%.