| 82% |
Stage #1: C6H8N2OS; C13H15BrFNO3 With dmap; copper(l) iodide; potassium carbonate; potassium iodide at 165 - 170℃; for 30h; Inert atmosphere;
Stage #2: With sodium hydroxide at 0 - 20℃; for 0.5h; Inert atmosphere;
Stage #3: 2-cyano-3-trifluoromethyl-5-bromopyridine at 175 - 180℃; for 36.5h; Inert atmosphere; |
1-3
Add tert-butyl N-(4-bromo-2-fluorobenzoyl)carbamate (996.5mg, 3.00mmol) to N-methylpyrrolidone (NMP, 5mL) solvent,Cuprous iodide (85.7mg, 0.45mmol), potassium iodide (99.6mg, 0.60mmol), 4-dimethylaminopyridine (73.3mg, 0.60mmol), potassium carbonate (497.6mg, 3.60mmol) and 6-thio -5,7-diazaspiro[3.4]octyl-8-one (492.0mg, 3.15mmol), replaced with nitrogen three times, heated to 165-170°C, and kept for 30h. After the incubation is over, cool to room temperature, cool to 0-5 in ice bath, add sodium hydrogen (60%, 240.0mg, 6.00mmol), keep at room temperature and stir for 30min, then add 2-cyano-3-trifluoromethyl-5 -Bromopyridine (787.6mg, 3.15mmol) in N-methylpyrrolidone (1mL) solution, after dripping, keep for 30min, raise the temperature to 175-180, keep the reaction for 36h, after the reaction, cool down to 0-5, 0.5 mL of saturated ammonium chloride solution was added dropwise to the reaction solution, and the mixture was stirred and kept for 30 minutes. The reaction solution was added dropwise to 10 mL ice water, the internal temperature was controlled at 5-15°C, after the addition, the temperature was kept and stirred for 30 min, filtered, and the filter cake was vacuum dried to obtain a brown crude product, which was purified by column chromatography (eluent: EtOAc:PE =0-2%) to obtain a white solidN-(4-(7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]-5 -Octyl)-2-fluorobenzoyl)-N-methylcarbamic acid tert-butyl ester(1420.9mg, 82%, purity 99%). |
| 78% |
Stage #1: C6H8N2OS; C13H15BrFNO3 With dmap; copper(l) iodide; potassium iodide; sodium hydroxide at 0 - 105℃; for 31h; Inert atmosphere;
Stage #2: 2-cyano-3-trifluoromethyl-5-bromopyridine at 175 - 180℃; for 36.5h; Inert atmosphere; |
4-5
To the N-methylpyrrolidone (NMP, 3mL) solvent was added cuprous iodide (85.7mg, 0.45mmol), potassium iodide (99.6mg, 0.60mmol), 4-dimethylaminopyridine (73.3mg, 0.60mmol) and Tert-butyl N-(4-bromo-2-fluorobenzoyl)carbamate (996.5mg, 3.00mmol), protected by nitrogen, cooled to 0-5°C in an ice bath, added sodium hydrogen (60%, 132.0mg, 3.30 mmol), 6-thio-5,7-diazaspiro[3.4]octyl-8-one (492.0mg, 3.15mmol) in NMP (2mL) solution was added dropwise, after the addition, the temperature was raised to 20- At 25°C, keep stirring for 30min, increase the temperature and heat to 100-105°C, keep holding for 30h.After the incubation is over, cool to room temperature, cool to 0-5°C in ice bath, add sodium hydrogen (60%, 144.0mg, 3.60mmol), keep at room temperature and stir for 30min, then add 2-cyano-3-trifluoromethyl-5 -Bromopyridine (787.6mg, 3.15mmol) in N-methylpyrrolidone (1mL) solution, after dripping, keep for 30min, raise the temperature to 175-180, keep the reaction for 36h, after the reaction, reduce the temperature to 0-5, 0.5 mL of saturated ammonium chloride solution was added dropwise to the reaction solution, and the mixture was kept warm and stirred for 30 min. The reaction solution was added dropwise to 10 mL ice water, the internal temperature was controlled at 5-15°C, after the addition, the temperature was kept and stirred for 30 min, filtered, and the filter cake was vacuum dried to obtain a brown crude product, which was purified by column chromatography (eluent: EtOAc:PE =0-2%) to obtain white solid N-(4-(7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7 -Diazaspiro[3.4]-5-octyl)-2-fluorobenzoyl)-N-methylcarbamic acid tert-butyl ester (1351.5 mg, 78%, purity 99%). |
Chemistry
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