3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine → 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246740Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 246740
[F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13]CCN(C)C)[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1

Komponenten

6

Edukt 2

HCID 712800443-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amineHCID 866780102-Bromo-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Produkt 1

HCID 712799912-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideAusbeute 9 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (13 mg, 9%). LCMS: (M+H)+=472; 1H NMR (300 MHz, CD3OD): δ 9.11 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 7.38 (d, 1H, J=8.7 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.85-4.78 (m, 2H), 4.65-4.60 (m, 1H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.50-2.40 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H).

Aufarbeitung

  1. customthe reaction mixture was degassed
  2. customby bubbling nitrogen for 3 minutes
  3. additionrefilled with nitrogen
  4. temperatureafter cooling to room temperature
  5. additionwater (50 mL) was added
  6. extractionproduct extracted with EtOAc (3×40 mL)
  7. dry with materialthe combined organic layers were dried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customthe residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm

Quellen und Nachweise

ORD-Eintrag
ord-c8f37d7a99c44bc3b9ef47dd7f7e2c20
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

Notizen zur Reaktion

Wird geladen…