In this study,the synthetic method of sparsentan(1)was improved.With 4-bromo-3-methylbenzo-nitrile(2)as the starting material,3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(6)was obtained via free radical substitution,nucleophilic substitution,cyano reduction,Miyaura borylation.In another way,the condensation of 2-bromobenzenesulfonyl chloride(7)with 3-amino-4,5-dimethylisoxazole(8)was conducted,followed by the amino-protection to give 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-[(2-methoxyethoxy)methyl]benzene-sulfonamide(11).Intermediates 6 and 11 reacted via Suzuki coupling reaction to get N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-4'-formyl-N-[(2-methoxyethoxy)methyl]-[1,1'-biphenyl]-2-sulfonamide(12),then the target compound 1 was obtained from compound 12 via reduction,bromination,condensation and deprotection.The total yield was about 43.25％(based on 2)with the purity of 99.5％.The optimized route avoided the usage of the dangerous and toxic reagents such as n-butyl lithium and carbon tetrabromoide,and simplified some purifications.
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