| 14% |
|
(Example 99) 3-[1-(5-Cyclopropylpyridin-2-yl)piperidin-4-yl]-4-hydroxy-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one[0795] 4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (385 mg, 1.27 mmol) produced in Reference Example 116, and N,N-diisopropylamine (323 µL, 1.90 mmol) in dimethyl sulfoxide (3 mL) was stirred while irradiated with microwaves at 60C for 1.5 hours using Initiator(R) manufactured by Biotage Japan Ltd. The reaction solution was poured to water, and the precipitate was collected by filtration and dried at 60C under reduced pressure to obtain a crude product (345 mg).[0798] A suspension of a portion (140 mg) of the obtained crude product and iron (71.5 mg, 1.28 mmol) in acetic acid (5 mL) was stirred at 70C for 1 hours and 50 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The resulting solid was filtered off. The filtrate was washed with a saturated sodium bicarbonate aqueous solution and brine in this order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol = 95/5 - 80/20 (gradient)] and further purified by silica gel chromatography [elute: hexane/ethyl acetate = 88/12 - 0/100 (gradient)] to obtain the title compound (37.2 mg, yield: 14%).[0799] 1H-NMR (DMSO-d6) δ: 12.22 (1H, s), 10.49 (1H, s), 7.96 (1H, d, J = 2 Hz), 7.20 (1H, dd, J = 9, 2 Hz), 6.77 (1H, d, J = 9 Hz), 6.72 (1H, s), 4.41-4.32 (2H, m), 3.25-3.15 (1H, m), 2.89 (1H, d, J = 16 Hz), 2.76-2.68 (2H, m), 2.72 (1H, d, J = 16 Hz), 1.90-1.62 (4H, m), 1.30-1.20 (1H, m), 0.88-0.83 (2H, m), 0.60-0.54 (2H, m); MS (ESI) m/z: 422 (M+H)+. |
| 14% |
|
5-Cyclopropyl-2- fluoropyridine (compounds described in WO2008 / 76 705 pamphlet, 209mg, 1.52mmol) in dichloromethane (3 mL) solution of hydrogen peroxide urea (301 mg, 3.20 mmol) and trifluoroacetic acid anhydride thing (426μL, 3.04mmol) was added, and the mixture was stirred overnight.After the reaction mixture was diluted with dichloromethane, saturated sodium hydrogen carbonate aqueous solution was washed successively with 10% aqueous sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The resulting residue, prepared in Reference Example 116 was 4-hydroxy-3- (piperidin-4-yl) -4- (trifluoromethyl) -1,4,5,7- tetrahydro -6H- pyrazolo [3 , 4-b] pyridin-6-one (385mg, 1.27mmol), and, N, N- diisopropylamine (323μL, 1.90mmol) of dimethyl sulfoxide (3 mL) solution Biotage Inc. the Initiator (TM) of using, 60 , and the mixture was stirred while being irradiated for 1.5 hours microwave.The reaction mixture was poured into water, collected by filtration and the resulting solid, dried under reduced pressure at 60 , was obtained (345mg).A portion of the resulting crude product (140 mg), and iron (71.5 mg, 1.28 mmol) and acetic acid (5 mL) suspension and stirred for 1 hour 50 minutes at 70 C..The solvent was distilled off under reduced pressure, ethyl acetate was added and the resulting solid was filtered off, the filtrate a saturated aqueous sodium hydrogen carbonate solution, successively washed with saturated brine, dried over anhydrous sodium sulfate under reduced pressure, the solvent It was distilled off.The obtained residue was purified by silica gel column chromatography [NH- silica gel column, eluent: ethyl acetate / methanol = 95 / 5-80 / 20 (gradient)] to give the further silica gel chromatography [eluent: hexane / acetic acid ethyl = 88 / 12-0 / 100 and purified by (gradient)] to give the title compound (37.2 mg, yield: 14%) was obtained.1H-NMR (DMSO-d-. 6) [delta] |
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