Ofloxacin → Ethyl 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

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Hayakawa's method of preparation of Ofloxacin is described in EP 0047005A1 and starts with 2,3,4-trifluoronitrobenzene which is converted to the 2-hydroxy-3,4-difluoronitrobenzene in dimethylsulfoxide in the presence of potassium hydroxide. The yield for this reaction is only 29%. The low yield of this step limits the overall yield of Hayakawa's process. Other patents cite the use of this material in their routes to Ofloxacin; e.g. U.S. Pat. No. 5,136,059 and EP 0333815 A2. The 2-hydroxy-3,4 difluoronitrobenzene is converted to 2-acetonyloxy-3,4-difluoronitro-benzene which is reductively ring closed to give an isomeric mixture of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine (Formula 1). This material is converted to diethyl-(7,8-difluoro-2,3-dihydro-3-methyl 4H 1,4 benzoxazinyl) methylenemalonate by reaction with diethylethoxymethylenamalonate. Cyclization of this malonate ester in ethylpolyphosphate gives (+,-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. This benzoxazine carboxylate ester is then hydrolyzed to the corresponding acid. The acid is reacted with N-methylpiperazine in dimethylsulfoxide to form Ofloxacin, 9-fluoro-10-(4-methyl-1-piperazinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. The reaction sequence is shown below: ##STR1##

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