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0 °C

Ethyl 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.414 g, 4.39 mmol) was suspended in 35% aqueous sulfuric acid solution (15 ml), and while cooling with ice, an aqueous sodium nitrite solution (394 mg, 5.70 mmol/4.5 ml) was dripped therein over a period of 5 minutes. After then stirring at 0° C. for 30 minutes, a small amount of urea was added, and at the same temperature, an aqueous copper (II) nitrate trihydrate solution (17.00, 70.2 mmol/155 ml) was dripped therein over a period of 10 minutes. After stirring at 0° C. for 5 minutes, copper (I) oxide (565 mg, 3.95 mmol) was added while stirring the reaction solution violently. After then stirring at room temperature for 20 minutes, extraction into chloroform (200 ml×2) was performed, and after making the aqueous layer slightly basic with sodium bicarbonate, the aqueous layer was extracted with chloroform (150 ml×3). The combined organic layer was then dried over anhydrous sodium sulfate, and after removing the drying agent bt the filtration, the solvent was evaporated under a reduced pressure. The crude product obtained was then subject to a silica gel chromatography, thereby obtaining 297 mg (21%) of the title compound as a yellow powder from a chloroform:methanol=10:1 eluate.

1. temperaturewhile cooling with ice
2. waitover a period of 10 minutes
3. stirringAfter stirring at 0° C. for 5 minutes
4. stirringwhile stirring the reaction solution violently
5. stirringAfter then stirring at room temperature for 20 minutes
6. extractionextraction into chloroform (200 ml×2)
7. extractionthe aqueous layer was extracted with chloroform (150 ml×3)
8. dry with materialThe combined organic layer was then dried over anhydrous sodium sulfate
9. customafter removing the drying agent
10. filtrationbt the filtration
11. customthe solvent was evaporated under a reduced pressure
12. customThe crude product obtained