| 53% |
|
[Reference Example 1-1] 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxo[2-14 C1]quinoline-3-carboxylic acid ethyl ester (compound A-1) A mixture (reaction liquid) of ethyl 3-(2,4,5-trifluoro-3-methoxy)phenyl-3-oxopropanate (1397.4 mg, 5.06 mmol), acetic anhydride (13.4 mL), and triethyl ortho[14C]formate (293 mCi, 851 muL, 758 mg, 5.05 mmol, density: 0.891 g/mL) was heated and refluxed for 1 hour under a nitrogen atmosphere. The reaction liquid was cooled to room temperature, toluene (17 mL) was added to the reaction liquid, and the obtained mixture was concentrated under reduced pressure using a rotary evaporator. To the residue, toluene (17 mL) was added, and the mixture was concentrated under reduced pressure using a rotary evaporator. This operation was repeated 4 times, to obtain a yellow oily product. To the residue as the obtained oily product, dimethylsulfoxide (13.4mL),<strong>[460-08-2]2-fluoroethylamine hydrochloride</strong> (1259.84mg, 12.7mmol), and potassium carbonate (1745.4 mg, 12. 6 mmol) were added to obtain a reaction liquid. The reaction liquid was stirred at 47C for 3 hours under a nitrogen atmosphere. To the reaction liquid, potassium carbonate (1752.9 mg, 12.7 mmol) was added, and the mixture was stirred at 78C for 1 hour, and then stirred at room temperature overnight, to obtain a reaction liquid. To the reaction liquid, water (50.5 mL) and acetone (8.4 mL) were added, and the mixture was stirred at room temperature for 20 minutes, and then stirred at 0C for 30 minutes, to obtain a precipitate. The precipitate was collected by filtration, and washed twice with a mixed liquid (5 mL) of water and acetone (water:acetone = 6:1). The resulting solid was dried under reduced pressure to obtain 1286.8 mg of crude product. To the obtained crude product, ethanol (24 mL) was added. The mixture was heated and refluxed under a nitrogen atmosphere until the solid was completely dissolved. The mixed solution was gradually cooled to room temperature, and water (5 mL) was added. After that, the mixture was stirred at room temperature for 20 minutes, and stirred at 10 to 15C for 30 minutes, to obtain a precipitate. The precipitate was collected by filtration, and washed twice with ethanol (1.6 mL). The solid was dried at 40C until the mass was constant. To the obtained solid, ethanol (21.8 mL) was added, and the mixture was heated and refluxed under a nitrogen atmosphere until the solid was completely dissolved. The obtained solution was gradually cooled to room temperature, and stirred at 10 to 15C for 30 minutes, to obtain a precipitate. The precipitate was collected by filtration, washed twice with ethanol (1.4 mL), and dried at 35 to 40C for 1 hour under reduced pressure. This operation was repeated twice or more to obtain 878.97 mg (2.65 mmol, 153.8 mCi, yield: 53%) of 14C-6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxo[ 2-14C1]quinoline-3-carboxylic acid ethyl ester (compound A-1). |
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