A suspension of 308.3 mg (2.0 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 560.5 mg (2.0 mmol) of 5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1) in 10 mL of ethanol under argon is stirred at room temperature for 1 hour. 1,3-Cyclohexanedione (224.3 mg, 2.0 mmol) is then added and the reaction mixture is heated at reflux temperature for 16 h. The mixture is then cooled in an ice bath and the precipitate is filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/cyclohexane 50/50 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is recrystallized from ethyl acetate/n-heptane and then from ethyl acetate, filtered and dried under reduced pressure. 189 mg of 9-[5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as an off-white crystalline powder. mp: 160-170° C. LCMS: m/z 511: [M+H]+ (base peak); m/z 509: [M−H]− (base peak). The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 220 mg of additional 9-[5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as an off-white powder. mp: 160-170° C. LCMS: m/z 511: [M+H]+ (base peak); m/z 509: [M−H]− (base peak).
