4-Fluoroindoline-2,3-dione

General procedure: After setting a reaction vessel equipped with a stirring device, a thermometer and a reflux condenser tube to a nitrogen gas atmosphere, 10.0 g (0.0723 mol) of 4-fluoroindole A was added, 200 ml of DMSO was added and dissolved. next, The interior of the container was evacuated to 800 mmbar, NBS (N-bromosuccinimide)26.5 g (0.149 mol) was slowly added, The temperature was raised to 80 ° C. for reaction. The progress of the reaction was measured by LC (Agilent 1200 Agilent Technology) and GC-MS (manufactured by Shimadzu Corporation, GC - MS 2010 PLUS)Pigment by mono Br body (4-fluoro-3-bromoindole)When it disappeared (about 3 hours after the start of the reaction), as a reaction stopper, 29.3 g (0.37 mol) of pyridine was added, and the mixture was further stirred for 2 hours.After that, the mixture was allowed to cool to room temperature, 500 ml of ethyl acetate was added, Followed by washing by adding 3percent aqueous sodium thiosulfate solution. next, The organic layer was separated, dehydrated by adding magnesium sulfate, filtered, concentrated, Silica gel column chromatography (toluene: ethyl acetate = 4: 1)To obtain 4-fluoroisatin A. In Example 2, 4-fluoroisatin E was synthesized in the same manner as in except that 4-fluoroindole B was changed to 4-fluoroindole E obtained above.1.0 g (0.0055 mol) of the above-obtained 4-fluoroisatin intermediate A was slowly added to 10 ml of concentrated sulfuric acid at 60 C. Thereafter, the reaction was carried out at 60 C. for 5 hours. After completion of the reaction, the reaction solution was poured into 200 g of ice water and reprecipitation was carried out, followed by filtration, and washing was carried out four times with 20 ml of ion exchanged water on the filter. The obtained crystals were dried under reduced pressure at 80 C. to synthesize 4-fluoroisatin M.The 4-fluoroisatin M obtained above was analyzed by 1 H-NMR (ECA 400, manufactured by JEOL Ltd.), The production ratio of 4-fluoroisatin: 6-fluoroisatin wasIt was about 15:85, which made it difficult to purify(1) Put 50g of chloral hydrate, 350g of anhydrous sodium sulfate and 500ml of water into a 1L three-necked bottle, heat to 35 C, stir to dissolve, add 30.8g of m-fluoroaniline, 61g of hydroxylamine hydrochloride, and 100ml of concentrated hydrochloric acid, and heat up to The reaction was performed at 85 C. for 4 hours. After the reaction was completed, the temperature was lowered and suction filtered. The filter cake was washed with a small amount of water and dried to obtain 46.4 g of a light yellow solid with a molar yield of 92%.(2) Take 36.4g of the above pale yellow solid and put it into a three-necked flask, add 200ml of 86% sulfuric acid, and raise the temperature to 80 C for 1 hour. After the reaction is completed, cool down in an ice bath. The reaction solution is poured into 120ml of water and an orange-red solid precipitates. Suction filtration, the filter cake was washed with a small amount of water, the filtrate was extracted with 200 ml of ethyl acetate, and the ethyl acetate was spin-dried. The obtained solid was combined with the filter cake to obtain 28.4 g of a mixture of (1) Put 50g of chloral hydrate, 350g of anhydrous sodium sulfate and 500ml of water into a 1L three-necked bottle, heat to 35 C, stir to dissolve, add 30.8g of m-fluoroaniline, 61g of hydroxylamine hydrochloride, and 100ml of concentrated hydrochloric acid, and heat up to The reaction was performed at 85 C. for 4 hours. After the reaction was completed, the temperature was lowered and suction filtered. The filter cake was washed with a small amount of water and dried to obtain 46.4 g of a light yellow solid with a molar yield of 92%.(2) Take 36.4g of the above pale yellow solid and put it into a three-necked flask, add 200ml of 86% sulfuric acid, and raise the temperature to 80 C for 1 hour. After the reaction is completed, cool down in an ice bath. The reaction solution is poured into 120ml of water and an orange-red solid precipitates. Suction filtration, the filter cake was washed with a small amount of water, the filtrate was extracted with 200 ml of ethyl acetate, and the ethyl acetate was spin-dried. The obtained solid was combined with the filter cake to obtain 28.4 g of a mixture of