Asymmetric Reduction Studies Of Indacaterol Intermediates

Alkali metal borohydride,as a mild,inexpensive,highly selective and environmentally friendly reducing agent,has been widely used in reduction reactions.For different types of functional groups,alkali metal borohydrides have extremely high reduction efficiency.However,the directly catalyzed asymmetric borohydride reduction reaction is relatively rare.It is a long-term challenge for chemists to obtain high enantioselectivity while maintaining high yields in asymmetric reduction reactions.Clinical studies have shown that COPD（chronic obstructive pulmonary disease）is a common frequently-occurring disease in respiratory diseases,and it is the most common cause of chronic pulmonary heart disease and chronic respiratory failure.Over the years,its prevalence and mortality constant increase.β2 receptor agonists can significantly relieve bronchospasm,and indacaterol maleate,as a new long-actingβ2receptor agonist,is mainly used for the maintenance treatment of COPD in clinical practice.This topic mainly adopts a new type of aminophenol sulfonamide ligand designed and synthesized in the laboratory,and successfully used it to catalyze the asymmetric reduction reaction of indacaterol intermediate A.After a series of screenings,such as the optimization and screening of reaction conditions such as the central metal,the ratio of metal to ligand,solvent,temperature,the amount of reducing agent,the type and amount of additives,and the amount of catalyst,the central metal Ni（TsO）₂and the amount of catalyst were optimized and screened.Ligand L9,under the combined action of 0.45 equivalent potassium borohydride reducing agent,22.5 u L isopropanol additive,and 1,4-dioxane solvent,catalytic reduction of indacaterol chiral intermediate A,92%Yield and 85%enantiomeric excess.And for the first time,the asymmetric reduction of indacaterol intermediate A with low-dose potassium borohydride as the reducing agent and metallic nickel has been achieved.