The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

The synthesis of [14C]-labeled clinafloxacin hydrochloride has been reported: The chlorination of 2,4,5-trifluorobromobenzene (I) with lithium diisopropylamide and hexachlorocyclopentadiene gives 3-chloro-2,4,5-trifluorobromobenzene (II), which is carbonated with 14CO2 and butyllithium in ether yielding 3-chloro-2,4,5-trifluoro-3-chlorobenzoic acid (III). The reaction of (III) with SOCl2 affords the corresponding acyl chloride (IV), which is condensed with the dilithium salt of the malonic acid monoethyl ester (V) to give the benzoylacetate (VI). The reaction of (VI) with acetic anhydride and ethyl orthoformate at 120-30 C yields the ethoxymethylene derivative (VII), which by treatment with cyclopropylamine affords the aminomethylene compound (VIII). The cyclization of (VIII) by means of potassium tert-butoxide in DMSO gives 1-cyclopropyl-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carbox ylic acid (IX), which is condensed with N-[pyrrolidin-3(S)-yl]carbamic acid tert-butyl ester by means of triethylamine in hot DMSO yielding the protected final product (XI). Finally, this compound is deprotected with 12N HCl in THF.