The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.

The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (+)-(XV) is obtained by HPLC chromatography of (XIV) on a chiral stationary phase. Treatment of (+)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (+)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane, and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which is then converted into (IX) by means of benzoyl chloride (VIII) in pyridine. Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (-)-(XV) is then obtained by HPLC chromatography on a chiral stationary phase. Treatment of (-)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (-)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.