N-methyl-2-pyrrolidone → HCID 71295688, compound

A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (25.0 g, 154 mmol), 1-methyl-2-pyrrolidinone (500 mL) and 4-bromo-2-fluorobenzaldehyde (31.2 g, 154 mmol). The mixture was stirred at rt for about 14 h then potassium 2-methylpropan-2-olate (18.98 g, 169 mmol) was added. The mixture was stirred for about 1 h then a second portion of potassium 2-methylpropan-2-olate (17.25 g, 154 mmol) was added. The mixture was stirred for about 15 min then warmed in an oil bath heated to about 160° C. for about 24 h. The mixture was cooled to rt then about 250 mL solvent was removed under reduced pressure. The mixture was diluted with about 750 mL water then allowed to stand overnight. The supernatant was decanted and the resulting residue was stirred with EtOAc (350 mL) for about 1 h. The solids were collected by filtration. The filtrate was concentrated then stirred in a mixture of DCM (350 mL), water (250 mL) and 6 N HCl (25 mL) for about 3 h. The layers were separated then the organic layer was dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to give a solid which was treated with heptane (100 mL) and stirred overnight at room rt. The solids were collected by filtration and washed with heptane (25 mL). The solids from the initial EtOAc trituration and the material from the column and heptane trituration were combined to yield 6-bromo-1-(4-fluorophenyl)-1H-indazole (1, R1=4-fluorophenyl) (23.94 g, 54%); LC/MS, method 3, Rt=2.83 min, MS m/z 291, 293 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.97 (s, 1H), 7.88-7.79 (m, 3H), 7.46-7.42 (m, 3H).

1. stirringThe mixture was stirred for about 1 h
2. stirringThe mixture was stirred for about 15 min
3. temperaturethen warmed in an oil bath
4. temperatureheated to about 160° C. for about 24 h
5. temperatureThe mixture was cooled to rt
6. customabout 250 mL solvent was removed under reduced pressure
7. additionThe mixture was diluted with about 750 mL water
8. waitto stand overnight
9. customThe supernatant was decanted
10. stirringthe resulting residue was stirred with EtOAc (350 mL) for about 1 h
11. filtrationThe solids were collected by filtration
12. concentrationThe filtrate was concentrated
13. stirringthen stirred in a mixture of DCM (350 mL), water (250 mL) and 6 N HCl (25 mL) for about 3 h
14. customThe layers were separated
15. dry with materialthe organic layer was dried over MgSO4
16. filtrationfiltered
17. concentrationthe filtrate concentrated under reduced pressure
18. customThe residue was purified on silica gel (330 g)
19. concentrationconcentrated under reduced pressure
20. customto give a solid which
21. stirringstirred overnight at room rt
22. filtrationThe solids were collected by filtration
23. washwashed with heptane (25 mL)

ORD record

ord-0b88bb088bab4ee3985e93220d611e0c

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2