1. In a 2L ChemGlass reactor equipped with a mechanical stirrer, temperature probe and cooling/heating circulator, N,N-dimethylformamide (540.0 mL, 6980 mmol, 100 wt%) was added.
2. 7-Fluorodihydroindole-2,3-dione (135.0 g, 817.6 mmol, 100 wt%) was added to the reactor at 25 °C and stirred until completely dissolved to form a deep red solution. Rinse the charging port and beaker with N,N-dimethylformamide (135.0 mL, 1750 mmol, 100 wt%) and add the rinse solution to the reactor.
3. 60-80 mesh cesium carbonate (203.66 g, 625.05 mmol, 100 wt%) was added to the reaction mixture in batches, noting that the addition process was exothermic, with the temperature increasing from 20 °C to 25.5 °C and the color of the solution changing from dark red to black. Set the reactor jacket temperature to 0 °C.
4. Slowly add iodomethane (56.5 mL, 907 mmol, 100 wt%) through a dropping funnel at ambient temperature, controlling the reaction temperature to be lower than 30 °C. The reaction is exothermic with the temperature rising from 20 °C to 25.5 °C. The temperature is set to 0 °C. The reaction was exothermic during addition and the temperature rose to 29.3 °C. After the addition of 85% iodomethane, the temperature dropped to 26.3 °C and the color of the reaction mixture changed from black to orange. After addition, the jacket temperature was raised to 25.5 °C.
5. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then transferred to a 1 L Erlenmeyer flask. The solid Cs2CO3 and other by-products were removed by filtration through a ceramic Brinell funnel fitted with No. 1 Whatman filter paper. The filter cake was washed with N,N-dimethylformamide (100.0 mL, 1290 mmol, 100 wt%) and the filtrate was collected in a 2L Erlenmeyer flask.
6. Water (3000.0 mL, 166530 mmol, 100 wt%) was added to a 5L ChemGlass reactor and 1.66 g of 7-fluoro-1-methyldihydroindole-2,3-dione was added as a crystalline seed to form an orange suspension.
7. The DMF filtrate was slowly added to a 5 L reactor, the temperature was controlled to be below 29 °C for 60 min, and the stirring speed was kept at 290 rpm. an orange solid precipitated immediately. Rinse the 2L conical flask with N,N-dimethylformamide (55.0 mL, 711 mmol, 100 wt%) and add the rinse solution to the 5L reactor.
8. The slurry was cooled to 25 °C and stirred at 200 rpm for 12 h to maintain as a bright orange suspension. It was then filtered through No. 1 Whatman filter paper in a 9 cm diameter ceramic Brinell funnel and collected in a 4L conical flask to obtain a bright orange filter cake.
9. The 5L reactor was rinsed with 1200 mL of water (400 mL in two batches) and the filter cake was washed directly with 300 mL of deionized water. The wet filter cake was dried by suction at ambient temperature for 40 minutes until no liquid dripped.
10. The filter cake was placed in a vacuum oven (800 mbar) and purged with nitrogen at ambient temperature for 1 h, then dried at 40-45 °C overnight, and finally purged at 25 °C for 1 day to afford 7-fluoro-1-methyl dihydroindole-2,3-dione (130.02 g, 725.76 mmol, 100 wt%, 88.77% yield) as a bright orange solid .
NMR (400 MHz, DMSO-d6) δ 7.57 (ddd, J = 12.0, 8.5, 1.0 Hz, 1H), 7.40 (dd, J = 7.3, 1.0 Hz, 1H), 7.12 (ddd, J = 8.5, 7.5, 4.0 Hz, 1H), 3.29 (d, J = 3.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 182.3, 158.2, 148.8, 146.4, 137.2, 125.9, 124.3, 120.6, 28.7.
