Alkylation of 5-hydroxy-2-nitrobenzaldehyde (I) with ethyl 4-bromobutyrate (II) in the presence of potassium carbonate at 110 C in DMF provided the aldehyde (III). Coupling of (III) with the phosphonate (IV) using triethylamine as the base afforded the unsaturated hydantoin derivative (V) as a mixture of geometrical isomers. Exhaustive catalytic hydrogenation of (V) over palladium on charcoal in DMF furnished the saturated aniline (VI), which underwent acid-catalyzed cyclization-dehydration in methanol at reflux, followed by oxidation upon addition of a molar equivalent of iodine to give the imidazo[4,5-b]quinoline derivative (VII). Alkaline hydrolysis of (VII) provided acid (VIII), which was coupled with N-cyclohexylmethylpiperazine, using diphenylphosphoryl azide in DMF at room temperature, to furnish BMY 43351 (IX). The dihydrochloride salt of (IX) was prepared by dissolution of the free base in a solution of 10% hydrogen chloride in methanol and subsequent precipitation with diethyl ether.

Alkylation of 5-hydroxy-2-nitrobenzaldehyde (I) with ethyl 4-bromobutyrate (II) in the presence of potassium carbonate at 110 C in DMF provided the aldehyde (III). Coupling of (III) with the phosphonate (IV) using triethylamine as the base afforded the unsaturated hydantoin derivative (V) as a mixture of geometrical isomers. Exhaustive catalytic hydrogenation of (V) over palladium on charcoal in DMF furnished the saturated aniline (VI), which underwent acid-catalyzed cyclization-dehydration in methanol at reflux, followed by oxidation upon addition of a molar equivalent of iodine to give the imidazo[4,5-b]quinoline derivative (VII). Alkaline hydrolysis of (VII) provided acid (VIII), which was coupled with N-cyclohexylmethylpiperazine, using diphenylphosphoryl azide in DMF at room temperature, to furnish BMY 43351 (IX). The dihydrochloride salt of (IX) was prepared by dissolution of the free base in a solution of 10% hydrogen chloride in methanol and subsequent precipitation with diethyl ether.