N,N-Dimethyl-1,3-propanediamine → N'-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamine

HRID 909219

Reaktionsgleichung

Reaktionsgleichung von HRID 909219
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2

Komponenten

7

Edukt 4

HCID 7993N,N-Dimethyl-1,3-propanediamineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 574187626-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole

Produkt 1

HCID 57639704N'-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamineAusbeute 69,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of 6-bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (15d; Example 110, Steps A-E) (0.030 g, 0.079 mmol), 3-(dimethylamino)propylamine (0.012 g, 0.118 mmol), BINAP (0.009 g, 0.016 mmol), Pd2 dba3 (0.007 g, 0.008 mmol), and NaOtBu (0.008 g, 0.087 mmol), in dioxane were mixed in a flask and purged with N2 three times. The reaction mixture was then heated to 100° C. for 16 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and brine (20 mL). The aqueous phase was extracted with ethyl acetate and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica eluting with acetone/ether (1:1.5) with 0.2% triethylamine. The product was chromatographed again eluting with 5% MeOH in dichloromethane to afford 0.022 g of the product as colorless oil (69% yield). MS (ESI+) m/z 403 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 7.70 (s, 1H), 6.95 (m, 3H), 6.80 (m, 1H), 6.40 (s, 1H), 5.48 (br. s, 1H), 4.06 (d, 2H), 3.28 (m, 2H), 2.43 (m, 2H), 2.35 (m, 1H), 2.20 (s, 6H), 1.86 (m, 2H), 0.94 (d, 6H).

Aufarbeitung

  1. custompurged with N2 three times
  2. temperatureThe mixture was cooled to room temperature
  3. custompartitioned between ethyl acetate (20 mL) and brine (20 mL)
  4. extractionThe aqueous phase was extracted with ethyl acetate
  5. dry with materialthe combined organics were dried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was chromatographed on silica eluting with acetone/ether (1:1.5) with 0.2% triethylamine
  8. customThe product was chromatographed again
  9. washeluting with 5% MeOH in dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-003d2a904c614145be9a70b7dacdc417
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08017641B2

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