| Chronic obstructive pulmonary disease(COPD)is a common disease characterized by persistent airflow limitation.Because of the aging of the population,the increasing number of smokers and the increasing pollution,chronic obstructive pulmonary disease(COPD),the progressive disease,endangers people’s health.With the increasingly serious air pollution,the morbidity and mortality of chronic obstructive pulmonary disease(COPD)has exceeded lung infection,which has become a new problem faced by people in the twenty-first Century.Vilantrol is a long-lasting,highly selective beta 2-adrenoceptor agonist developed by GlaxoSmithKline Co.It is only needed once a day to treat COPD patients with ICS.On the basis of the characteristics of salmeterol,high efficacy,less adverse reactions outside the lungs,and little tolerance,vilantrol has faster onset,longer duration and higher selectivity,and is safe and well tolerated in patients with asthma and chronic obstructive pulmonary disease.Thus,vilantrol has a good market prospect.This paper is to improve the route to synthses is process of key chiral intermediates of vilantrol.According to the patent,use 5-(2-bromo acetyl)-2-hydroxy benzaldehyde as raw materials to get 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone,first through the origina 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol,followed by Gabriel reaction,2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol,the resulting product with 1,1’-Carbonyldiimidazole(CDI)into the ring to the racemic target product,then use L-(+)-tartaric acid to the split for obtaining the target product,the EE value is 90%.This paper also optimized the conditions of some processes.Through grouping comparison experiments,we compared the reaction time,reaction temperature,mol ratio and reaction solvent,obtained better reaction conditions and purification conditions,and finally achieved satisfactory results.Compared with patent published by GSK,the route(1)avoid the using of Di-tert-butyl imino dicarboxylate and Cesium carbonate which are expensive.And improved yield(2)avoid the using of toxic catalyst of chiral CBS(3)shorten the process,simplify the operation. |
