1-Bromo-2-methylpropane → 6-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole

HRID 1715610Notes

Reaction equation

HRID 1715610 reaction equation
[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]

Participants

5

Reactant 3

HCID 65551-Bromo-2-methylpropaneHCID 11430Potassium Carbonate2×HCID 574187616-Bromo-5-(2,4-difluorophenoxy)-1H-indazole

Product 1

HCID 574187626-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazoleYield 43%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

6-Bromo-5-(2,4-difluorophenoxy)-1H-indazole (60.0 g, 185 mmol) was dissolved in DMF and treated with K2CO3 (76.5 g, 554 mmol) and with isobutyl bromide (126.4 g, 923 mmol). The mixture was stirred and heated to 80° C. for 16 hours. An additional 15 g of K2CO3 were added and the mixture was vigorously stirred for 24 hours more. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and dissolved in ether (1 L). The mixture was washed with 1:5 brine/water (2×600 mL). The aqueous phases were extracted with ether (300 mL) and the combined organics were dried (MgSO4) and concentrated under reduced pressure. The crude product was chromatographed on a Biotage Flash 75 in two batches (about 35 g each) eluting with 5% ethyl acetate in hexanes. The combined purified products yielded 30.1 g of the desired product as a solid (43% yield). MS (ESI+) m/z 381, 383 (M+1, Br pattern) detected; 1H NMR (400 mHz, CDCl3) δ 7.86 (s, 1H), 7.72 (s, 1H), 7.16 (s, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 4.12 (d, 2H), 2.34 (m, 1H), 0.94 (d, 6H).

Workup

  1. stirringthe mixture was vigorously stirred for 24 hours more
  2. temperatureThe reaction mixture was then cooled to room temperature
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. dissolutiondissolved in ether (1 L)
  6. washThe mixture was washed with 1:5 brine/water (2×600 mL)
  7. extractionThe aqueous phases were extracted with ether (300 mL)
  8. dry with materialthe combined organics were dried (MgSO4)
  9. concentrationconcentrated under reduced pressure
  10. customThe crude product was chromatographed on a Biotage Flash 75 in two batches (about 35 g each)
  11. washeluting with 5% ethyl acetate in hexanes
  12. customThe combined purified products

Sources & evidence

ORD record
ord-197b1c50c95549ac9aef4e3a159aebc2
Source dataset
uspto-grants-2010_09
Patent number
US07799782B2

Reaction notes

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