反应详情

To a stirred solution of 5-(2,4-Difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (16.3 g, 44.7 mmol) in a mixture of DCM (180 mL) and DMF (60 mL) at ambient temperature was added HOBt hydrate (6.85 g, 44.7 mmol). Once all of the HOBt had dissolved, (S)-3-aminopyrrolidin-2-one 4.84 g, 48.3 mmol) was added. To the resulting stirred solution at ambient temperature was added EDC (9.43 g, 49.2 mmol), and the resulting cloudy mixture was stirred at ambient temperature. After stirring for a total of 24 hr the DCM was evaporated under reduced pressure. The residual DMF solution was stirred and diluted with water (300 mL), and the resulting mixture was stirred at ambient temperature. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the crude product (20.7 g, 104%). This material was combined with a second batch (37.8 g) and recrystallized as follows: The two batches were combined in a 1000 mL Erlenmeyer flask. Acetone (250 mL) was added, and the mixture stirred with gentle heating on a hot plate. All solid dissolved as the solution boiled (52° C.). While the solution was boiling and stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel. Shortly after completion of addition, the product began to crystallize. A second portion of hexanes (250 mL) was added slowly as crystallization continued. The resulting mixture was stored at 2° C. for 14 hr. The crystals that formed were collected by filtration, washed with cold 2:1 hexane:acetone, and dried under vacuum to afford the title compound as an off-white powder (48.2 g, 83% recovery). 1H NMR (CDCl3). δ 1.37 (d, J=2.8 Hz, 3H); 1.42 (d, J=3.2 Hz, 3H); 2.02-2.17 (m, 1H); 2.85-2.91 (m, 1H); 3.42-3.46 (m, 2H); 4.53-4.60 (m, 3H); 5.97 (broad s, 1H); 6.88-6.93 (m, 1H); 6.98-7.03 (m, 2H); 7.12-7.18 (m, 1H); 7.90 (s, 1H); 8.20 (d, J=5.2 Hz, 1H); 8.42 (s, 1H). MS (LC/MS/pos): 469.1 (M+Na)+. Chiral purity is >99% ee (done by chiral HPLC).

1. stirringthe resulting cloudy mixture was stirred at ambient temperature
2. customwas evaporated under reduced pressure
3. stirringThe residual DMF solution was stirred
4. additiondiluted with water (300 mL)
5. stirringthe resulting mixture was stirred at ambient temperature
6. customThe precipitate that formed
7. filtrationwas collected by filtration
8. washwashed with water
9. customdried under vacuum
10. customto afford the crude product (20.7 g, 104%)
11. customrecrystallized
12. additionAcetone (250 mL) was added
13. stirringthe mixture stirred
14. temperaturewith gentle heating on a hot plate
15. dissolutionAll solid dissolved as the solution
16. custom(52° C.)
17. stirringstirring on the hot plate, hexanes (250 mL, 20° C.)
18. additionwas added slowly from a separatory funnel
19. additionShortly after completion of addition
20. customto crystallize
21. additionA second portion of hexanes (250 mL) was added slowly as crystallization
22. customThe crystals that formed
23. filtrationwere collected by filtration
24. washwashed with cold 2:1 hexane
25. dry with materialacetone, and dried under vacuum