反应详情

温度

2.5 °C

To an inert 250 mL 3-neck round bottom flask with magnetic stirring was added LiHMDS (1M in THF, 57.3 mL, 57.3 mmol). The solution was cooled in an ice/brine bath to achieve an internal temperature of −4° C. To the cooled LiHMDS solution was added dropwise a solution of 2-chloro-5,6-difluoronicotinamide (4.41 g, 22.9 mmol) dissolved in 2-methyltetrahydrofuran (22 mL) and N,N-dimethylformamide (8.87 mL, 115 mmol) while maintaining the internal temperature between +1° C. to −3° C. The reaction mixture was stirred for 30 minutes at a temperature of about 0° C. The reaction was quenched by adding it dropwise to a cooled (0-5° C.) stirred mixture of 2M aqueous HCl (74.4 mL, 149 mmol) and IPAc (75 mL) while maintaining an internal temperature <10° C. Once the transfer was completed, the biphasic solution was transferred to a separatory funnel and the lower aqueous layer was removed and extracted with IPAc (75 mL). The organic layers were combined, washed with water (25 mL), dried over sodium sulfate, and concentrated on a rotary evaporator. The resulting solid was suspended in heptane (20 mL), and the mixture was stirred for 90 minutes and filtered. The filter cake was washed with heptane (20 mL) and dried to give the title compound as an off-white solid (4.442 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.11-6.14 (m, 1H), 6.98 (d, J=8 Hz, 1H), 9.5 (s br, 1H).

1. temperatureThe solution was cooled in an ice/brine bath
2. customan internal temperature of −4° C
3. stirringThe reaction mixture was stirred for 30 minutes at a temperature of about 0° C
4. customThe reaction was quenched
5. additionby adding it dropwise to
6. stirringstirred
7. temperaturewhile maintaining an internal temperature <10° C
8. customthe biphasic solution was transferred to a separatory funnel
9. customthe lower aqueous layer was removed
10. extractionextracted with IPAc (75 mL)
11. washwashed with water (25 mL)
12. dry with materialdried over sodium sulfate
13. concentrationconcentrated on a rotary evaporator
14. stirringthe mixture was stirred for 90 minutes
15. filtrationfiltered
16. washThe filter cake was washed with heptane (20 mL)
17. customdried