反应详情

温度

5 °C

A 22-L multi-neck RBF equipped with an overhead stirrer, temperature probe, and N2 inlet/outlet was charged with LiHMDS (10.65 L, 2.5 eq) by N2 pressure. The orange solution was cooled to <0° C. using an ice/brine bath. A separate 12-L RBF was sequentially charged with 2,6-dichloro-5-fluoronicotinamide (890 g, 1.0 eq), anhydrous THF (6.0 L), and anhydrous DMF (1.0 L, 3.0 eq). The resulting solution was added to the LiHMDS solution via a peristaltic pump over a 1 h period, which kept the internal temperature below 5° C. The 12-L flask was rinsed with THF (1.6 L), and the rinse was transferred to the reaction mixture. The mixture was stirred at a temperature<5° C. for 1 h, and the reaction was added to a pre-cooled 2N HCl aq solution via a peristaltic pump at a rate that kept the temperature of the mixture below 22° C. Following the quench, IPAc (14 L) was added and the mixture was stirred for 10 min. The biphasic mixture was separated and the organic layer was stored in a carboy at RT overnight. The organic layer was subsequently washed with water (8.9 L) and was concentrated under reduced pressure to a volume of about 4.5 L. The distillation was continued the next day. Isopropyl acetate (16 L) was added to the slurry and the distillation was continued until about 4.5 L of material remained. The off-white slurry was transferred into a 50-L multi-neck RBF to which was charged heptanes (18 L) via a peristaltic pump over a 45 min period. The resultant slurry was stirred at RT overnight and then filtered through a Buchner funnel with a Sharkskin filter paper. The filter cake was washed with heptanes (2×4.5 L) and then dried under high vacuum at RT for 24 h to afford title compound (913.0 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.11 (dd, J=9.3 Hz, 1.5 Hz, 1 H), 6.95 (d, J=9.3 Hz, 1 H), 9.54 (s, 1 H). [M+H] calc'd for C7H3Cl2FN2O2, 237; found, 237.

1. customA 22-L multi-neck RBF equipped with an overhead stirrer
2. temperatureThe orange solution was cooled to <0° C.
3. customthe internal temperature below 5° C
4. washThe 12-L flask was rinsed with THF (1.6 L)
5. additionthe reaction was added to a pre-cooled 2N HCl aq solution via a peristaltic pump at a rate that
6. customthe temperature of the mixture below 22° C
7. additionwas added
8. stirringthe mixture was stirred for 10 min
9. customThe biphasic mixture was separated
10. waitthe organic layer was stored in a carboy at RT overnight
11. washThe organic layer was subsequently washed with water (8.9 L)
12. concentrationwas concentrated under reduced pressure to a volume of about 4.5 L
13. distillationThe distillation
14. additionIsopropyl acetate (16 L) was added to the slurry
15. distillationthe distillation
16. customThe off-white slurry was transferred into a 50-L multi-neck
17. additionRBF to which was charged heptanes (18 L) via a peristaltic pump over a 45 min period
18. stirringThe resultant slurry was stirred at RT overnight
19. filtrationfiltered through a Buchner funnel with a Sharkskin
20. filtrationfilter paper
21. washThe filter cake was washed with heptanes (2×4.5 L)
22. customdried under high vacuum at RT for 24 h