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.
2) The bromination of 3(R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran (XV) with Br2 in acetic acid gives the 8-bromo compound (XVI), which is protected with benzyl bromide and K2CO3 in acetonitrile, yielding the dibenzylamino compound (XVII). The reaction of (XVII) with N-fluorobenzenesulfonimide and BuLi in THF provides the corresponding 8-fluoro derivative (XVIII), which is deprotected with H2 over Pd/C in methanol/THF, giving 3(R)-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (XIX). The alkylation of (XIX) with cyclobutanone (XII) and sodium cyanoborohydride in methanol gives the dicyclobutylamino compound (XX), which is demethylated by means of boron tribromide in dichloromethane to afford the 5-hydroxy compound (XXI). The triflation of (XXI) with trifluoromethanesulfonic anhydride and collidine in dichloromethane yields the triflate (XXII), which is treated with carbon monoxide, palladium acetate and methanol to give methyl 3(R)-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (XXIII). The hydrolysis of (XXIII) with refluxing 6M aqueous HCl yields the free acid (XXIV), which by reaction with SOCl2 is converted into the acyl chloride (XXV). Finally, this compound is treated with ammonia in dichloromethane to give robalzotan (XIII).
The synthesis of [14C]-labeled robalzotan has been described: The treatment of 3(R)-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-benzopyran-5-ol (I), a known intermediate in the synthesis of robalzotan, with Tf2O in dichloromethane provides the triflate (II), which by reaction with [14C]-KCN and a Pd catalyst in N-methylpyrrolidine gives the labeled nitrile (III). Hydrolysis of nitrile (III) with refluxing HBr yields the carboxylic acid (IV), which by reaction with SOCl2 affords the corresponding acyl chloride (V). Finally, this acyl chloride (V) is treated with ammonia to provide [14C]-labeled robalzotan.
The synthesis of [3H]-labeled robalzotan has been described: The bromination of 3(R)-(dicyclobutylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-benzopyran (I), a previously described intermediate in the synthesis of robalzotan, with Br2 in ethanol affords the 6-bromo-8-fluorobenzopyran derivative (II), which is first demethylated with refluxing conc. HBr yielding the 5-hydroxy compound (III) and then treated with Tf2O in dichloromethane providing triflate (IV). The carbonylation of (IV) with CO and Pd(OAc)2 in DMF/methanol gives the methyl ester (V), which is hydrolyzed with refluxing HCl to yield the carboxylic acid (VI). The reaction of (VI) with SOCl2 affords the corresponding acyl chloride (VII), which is treated with ammonia to provide the carboxamide (VIII). Finally, this compound is hydrogenated with 3H2 catalyzed by PdO in DMF.