Study On New Process For Preparation Of Arformoterol By Convergent Strategy And Its Optimization

Chronic obstructive pulmonary disease（COPD）has become one of the significant factors affecting the death of COVID-19 patients,and began to be known by the public.According to the report released by GOLD in 2021,COPD has become a major global epidemic.By 2021,COPD become one of the top three causes of death in the world.Smoking habits,environmental pollution,occupational effects and genetic factors all contribute to the increa sing incidence of COPD and other diseases.Among many COPD-related drugs,formoterol is a kind ofβ₂-adrenoreceptor agonist,which not only has a long-acting effect,but also is the first choice for single or combined use of COPD.The arformoterol studied in this study is the dominant chiral configuration of formoterol,which is not only twice as effective as formoterol,but also has much lower side effects than formoterol.Meanwhile,all patents for arformoterol tartrate will expire in 2021.For this reason,a new route for the synthesis of arformoterol was designed in this paper.The new route uses low-cost 4-hydroxy-3-nitroacetophenone and N-Benzyl-1-（4-methoxyphenyl）propan-2-amine as starting materials.（R）-N-（2-（benzyloxy）5-（oxiran-2-yl）phenyl）formamide was synthesized from 4-hydroxy-3-nitroacetophenone by alkylation,bromination,catalytic reduction,amination,N formylation and epoxidation.Then（R）-N-Benzyl-1-（4-methoxyphenyl）propan-2-amine was easily obtained from N-Benzyl-1-（4-methoxyphenyl）propan-2-amine by chiral resolution agent,and arformoterol was obtained only by hydrogenation debenzylation after coupling of two important chiral intermediates.It takes only 8 steps to synthesize arformoterol,which not only effectively reduces the production time and economic cost,but also pays more attention to green environmental protection and reusability in the selection of reactants and related solvents.After many times of optimization,the overall yield of arformoterol was greatly increased,and the optical purity was≥99%.If this route can achieve industrial production,it will be able to meet the more affordable and effective drug needs of a large number of patients in the future.