A novel method for synthesis of fidarestat, an aldose reductase inhibitor, was developed. The key intermediate (S)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (8) was prepared starting from N-phenylmaleimide and 4-fluorophenol, which are inexpensive and easily available starting materials, via base-catalyzed oxo-Michael addition, hydrolysis, resolution with (S)-α-phenylethylamine and Friedel- Crafts acylation. Subsequently, fidarestat was synthesized from 8 through Bucherer-Bergs hydantonination reaction and amidation by using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM) as condensation reagent. The overall yield was about 22.4%. The structures of intermediates and final product were determined by ¹H NMR, ¹³C NMR, HRMS techniques, optical rotation and comparison with reported data. This method has the advantages of easily available starting materials, simply conducted procedures, relatively high yield and easy purification, and is more suitable for scale-up production.

Key words: aldose reductase inhibitor, fidarestat, (S)-2-(4-fluorophenoxy)succinic acid, (S)-6-fluoro-3,4- dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid, synthesis