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

HRID 912445

Reaktionsgleichung

Reaktionsgleichung von HRID 912445
[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]

Komponenten

5

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

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 isobutyl bromide (126.4 g, 923 mmol). The reaction 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 an additional 24 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and dissolved in ether (1 L). The ether layer was washed with 1:5 brine/water (2×600 mL). The aqueous phases were extracted with ether (300 mL) and the combined organic layers 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).

Aufarbeitung

  1. stirringthe mixture was vigorously stirred for an additional 24 hours
  2. temperaturecooled to room temperature
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. dissolutiondissolved in ether (1 L)
  6. washThe ether layer 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 organic layers 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

Quellen und Nachweise

ORD-Eintrag
ord-0210c988d5694cf8964c2f8143c6fab7
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08026233B2

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