合成路线1

1) The esterification of 4-fluoro-3-hydroxybenzoic acid (I) with trimethyl orthoformate and sulfuric acid gives the methyl ester (II), which is condensed with propargyl bromide (III) by means of K2CO3 in acetone, yielding the corresponding ether (IV). The cyclization of (IV) by heating at 220 C in N,N-diethylaniline affords 8-fluoro-2H-1-benzopyran-5-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VI). The reaction of (VI) with thionyl chloride and then with ammonia affords the carboxamide (VII), which is nitrated with NaNO2 and iodine, giving the 8-fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (VIII). The hydrogenation of the double bond of (VIII) with NaBH4 in isopropanol yields the 3,4-dihydro compound (IX), which is then further reduced at the nitro group with H2 and RaNi in ethanol/THF, providing racemic 3-amino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (X). Optical resolution of (X) with L-(+)-tartaric acid gives the 3(R)-amino derivative (XI), which is alkylated with cyclobutanone (XII) and sodium cyanoborohydride in methanol/acetic acid to afford robalzotan (XIII). Finally, this compound is treated with L-(+)-tartaric acid (XIV) in THF/ethyl ether.