反应详情

温度

60 °C

Thiophosgene (0.35 mL) was added dropwise to a solution of 4-((1-cyanocyclopentyl)amino)-2-fluoro-N-methylbenzamide (Intermediate 103, 400 mg, 1.53 mmol) and 5-amino-3-methylpicolinonitrile (Intermediate 2, 303 mg, 2.28 mmol) in DMA (30 mL) under N2 atmosphere. The resulting mixture was stirred at 60° C. overnight. MeOH (22 mL) and HCl (2M, 11 mL) were added and the mixture was refluxed for 2 h then cooled to room temperature. The reaction mixture was poured into water (75 mL) and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:5 EtOAc/petroleum ether), to afford 300 mg of 4-(3-(6-cyano-5-methylpyridin-3-yl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.47 (m, 1H), 8.17 (s, 1H), 7.78 (m, 1H), 7.55 (d, 1H), 7.41 (d, 1H), 2.81 (d, 3H), 2.60 (s, 3H), 2.29-2.21 (m, 4H), 1.72 (m, 2H), 1.41 (m, 2H). LCMS [M+1]+ 438.1.

1. temperaturethe mixture was refluxed for 2 h
2. temperaturethen cooled to room temperature
3. extractionextracted with EtOAc
4. dry with materialThe organic layer was dried over sodium sulfate
5. concentrationconcentrated in vacuo
6. customThe residue was purified by column chromatography on silica gel (1:5 EtOAc/petroleum ether)