Study On Synthesis Process Of Indacaterol Maleate

Chronic obstructive pulmonary disease（COPD）is a common respiratory disease.Currently,it ranks as the fourth leading cause of mortality across the globe.The Globe Burden of Disease Study predicted that the disease would be the third leading cause of the death worldwide by 2020.In China,the disease is of a high morbidity,disability and mortality,and having serious impacts on the people’s health and quality of life.The pathogenesis of COPD is very complex,the exact cause is still not very clear.So far,there is no specific treatment of this disease,mostly symptomatic treatment.Alleviating the airflow limitation is the main purpose to control the disease symptoms,and to reduce the frequency and severity of exacerbations,and then to improve exercise tolerance and quality of life.Due to the good activity in the expansion of trachea,β₂ receptor agonists have been in a dominant position in the treatment of COPD,and also been the focus of drug research and development.Indacaterol Maleate is developed by Novartis（a Swiss company）,it is the first ultra-long-acting β₂ receptor agonists to be used in clinical treatment with a rapid onset of action and a long time duration,allowing for once-daily administration,and it can control the patients’ wheezing symptons both of COPD and bronchial asthma well,and even improve the lung function.In addition,the systemic adverse reactions induced by this drug is less and mild,so Indacaterol Maleate is a ideal drug for the treatment of chronic obstructive pulmonary disease and bronchial asthma.In July of 2011,the Indacaterol Maleate Powder for Inhalation had got the Food and Drug Administration（FDA）approvement for the treatment of adult patients with COPD.In June of 2012,the State Food and Drug Administration（SFDA）approved the drug to enter the Chinese market,but the domestic product has not yet listed.In China,the compound patent of this drug will expire in 2020,and the demand of domestic market for this drug is quite large,so there is a broad market prospects to research and develop Indacaterol Maleate.By consulting some relevant literatures,the author firstly carried out a route screening of Indacaterol Maleate and evaluated,then explored and optimized the technological conditions of each reaction step,and finally determined a route of the synthesis which starting material was easy to obtain,procedure was simple,and was of a high yield,a good purity,and little pollutin,and also was suitable for industrial production.The synthesis of the target molecule started from 8-hydroxy-1H-quinolin-2-one,after the reaction of Fries Rearrangement,O-alkylation,α bromide substitution of ketone,asymmetric reduction of ketone carbonyl,intramolecular cyclizationthe,the key intermediate 2 was obtained,and then the epoxide reacted with compound 3 by N-alkylation reaction,without a separation procedure,and then reacting with benzoic acid to get the corresponding salt directly,that was the intermediate 4.Finally through the hydrogen to deprotect benzyl,and reacting with the maleic acid to get the final product of Indacaterol Maleate with a total yield of 43.8%.The chemical purity was 97.6%,and the optical purity was 99.0%.In addition,the stucture of each intermediate and the final product in this route were confirmed by the 1H-NMR and the qaulity was analyzed by HPLC homogenization.