反应详情

A 12 L round bottom flask is equipped with overhead agitation, a thermocouple, and a N2 purge. tert-Butyl 4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (404 g, 954.08 mmol) is dissolved in DMF (2 L) and charged to the flask. DMF (1 L) is used to rinse the flask. 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (259.46 g, 1.05 mol) and EDCI (228.63 g, 1.19 mol) are added and it is rinse in with DMF (500 mL). Then HOBt (189.94 g, 1.24 mol) is added and it is again rinsed in with DMF (500 mL). Finally, DIPEA is slowly added (184.97 g, 1.43 mol). The dark solution is then stirred at RT over the weekend. To a 20 L bottom outlet flask is added DI water (3 L) and DCM (5 L). The reaction mixture is poured in and it is rinsed in with DCM (1 L). The organic layer is separated, washed with DI water (3×3 L), dried over Na2SO4, filtered, rinsed solids with DCM and concentrated the filtrate. EtOAc (2 L) is added to the residue and the solution is stirred for 1 hour. The product crystallizes out. The mixture is concentrated. Another portion of EtOAc (2 L) is added and concentrated to remove all of the DCM. EtOAc (650 mL) and MTBE (3 L) are added to the residue and the solution is stirred in an ice bath for 1 hour. The tan slurry is filtered using a polypropylene pad. The cake is rinsed with MTBE (2×500 mL). The light tan solid is dried overnight in the vacuum oven at 40° C. to give the crude product (553 g). The crude product is purified by silica gel column chromatography eluting with (50% EtOAc (50%):35% DCM (35%): n-heptane (15%)) to give the pure desired product tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (424 g, 68%). MS (m/z): 651.0 (M−H).

1. customA 12 L round bottom flask is equipped with overhead agitation
2. customa thermocouple, and a N2 purge
3. additioncharged to the flask
4. washto rinse the flask
5. washit is rinse in with DMF (500 mL)
6. washit is again rinsed in with DMF (500 mL)
7. additionFinally, DIPEA is slowly added (184.97 g, 1.43 mol)
8. additionTo a 20 L bottom outlet flask is added DI water (3 L) and DCM (5 L)
9. additionThe reaction mixture is poured in and it
10. washis rinsed in with DCM (1 L)
11. customThe organic layer is separated
12. washwashed with DI water (3×3 L)
13. dry with materialdried over Na2SO4
14. filtrationfiltered
15. washrinsed solids with DCM
16. concentrationconcentrated the filtrate
17. additionEtOAc (2 L) is added to the residue
18. stirringthe solution is stirred for 1 hour
19. customThe product crystallizes out
20. concentrationThe mixture is concentrated
21. additionAnother portion of EtOAc (2 L) is added
22. concentrationconcentrated
23. customto remove all of the DCM
24. additionEtOAc (650 mL) and MTBE (3 L) are added to the residue
25. stirringthe solution is stirred in an ice bath for 1 hour
26. filtrationThe tan slurry is filtered
27. washThe cake is rinsed with MTBE (2×500 mL)
28. customThe light tan solid is dried overnight in the vacuum oven at 40° C.
29. customto give the crude product (553 g)
30. customThe crude product is purified by silica gel column chromatography
31. washeluting with (50% EtOAc (50%):35% DCM (35%): n-heptane (15%))