反应详情

To a solution of methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate 77 (prepared as in Example 3) (60.0 g, 184.4 mmol) in MeOH (370 mL) was added NaBH4 (24.42 g) in five 5 gram portions over 90 minutes. The temperature rose from 25° C. to 44.7° C. at the final addition of NaBH4. The mixture was concentrated under vacuum. To the concentrate was added saturated NH4Cl (600 mL) and EtOAc (600 mL) and the mixture was vigorously stirred for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with saturated NH4Cl (2×100 mL), water (200 mL), brine (500 mL), dried over MgSO4, filtered thru GF/F paper and concentrated to a bright orange solid. The crude solid was dissolved in CH2Cl2 (1 L) and hexanes (2.25 L) were added with stirring. A light brown solid formed and after stirring for 30 min the solid was collected and dried under high vacuum to yield 45.5 g. The filtrate was concentrated under reduced pressure. This material was redissolved in CH2Cl2 (100 mL) and hexanes were added (200 mL). The resulting solid (6.2 g) was collected via filtration. The two crops were combined to give 51.7 g (94.3%) of 78A. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.49 (d, 1H), 7.39-7.36 (m, 2H), 7.21-7.16 (m, 2H), 6.90 (dd, 1H), 4.49 (t, 2H), 4.17-4.13 (m, 2H), 2.81 (t, 1H).

1. customrose from 25° C. to 44.7° C.
2. concentrationThe mixture was concentrated under vacuum
3. additionTo the concentrate was added saturated NH4Cl (600 mL) and EtOAc (600 mL)
4. customThe layers were separated
5. extractionthe aqueous layer was extracted with EtOAc (2×100 mL)
6. washThe combined organics were washed with saturated NH4Cl (2×100 mL), water (200 mL), brine (500 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated to a bright orange solid
10. dissolutionThe crude solid was dissolved in CH2Cl2 (1 L)
11. additionhexanes (2.25 L) were added
12. stirringwith stirring
13. customA light brown solid formed
14. stirringafter stirring for 30 min the solid
15. customwas collected
16. customdried under high vacuum
17. customto yield 45.5 g
18. concentrationThe filtrate was concentrated under reduced pressure
19. dissolutionThis material was redissolved in CH2Cl2 (100 mL)
20. additionhexanes were added (200 mL)
21. filtrationThe resulting solid (6.2 g) was collected via filtration