Potassium Phosphate, Tribasic → N-(3-(4-(4-Amino-2-fluorophenoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)acetamide

HRID 2117127Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2117127
CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[CH:37]=[CH:38][N:39]2[C:44]=1[C:43]([O:45][C:46]1[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=1[F:53])=[N:42][CH:41]=[N:40]2.[C:54]([NH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1)(=[O:56])[CH3:55].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:52][C:49]1[CH:50]=[CH:51][C:46]([O:45][C:43]2[C:44]3=[C:36]([C:62]4[CH:63]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[CH:59]=[CH:60][CH:61]=4)[CH:37]=[CH:38][N:39]3[N:40]=[CH:41][N:42]=2)=[C:47]([F:53])[CH:48]=1

Komponenten

6

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 157274(3-Acetamidophenyl)boronic acid2×HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 210816684-(5-Chloropyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine

Produkt 1

HCID 21081735N-(3-(4-(4-Amino-2-fluorophenoxy)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)acetamideAusbeute 26,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 167845palladium(II) acetateKatalysator2×

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

A flask was charged with palladium acetate (4.5 mg, 0.02 mmol), X-Phos ligand (24 mg, 0.05 mmol, Strem), 4-(5-chloropyrrolo[2,1-f][I,2,4]triazin-4-yloxy)-3-fluorobenzenamine (56 mg, 0.20 mmol), 3-acetamidobenzene boronic acid (72 mg, 0.40 mmol, Lancaster), and potassium phosphate (127 mg, 0.60 mmol) in that order. The flask was flushed with nitrogen and then t-BuOH was added (0.40 mL). The mixture was heated at 80° C. for 8 h. Additional shots of palladium acetate (4.5 mg, 0.02 mmol), X-Phos ligand (24 mg, 0.05 mmol), and 3-acetamidobenzene boronic acid (72 mg, 0.40 mmol) were added and the reaction was stirred an additional 9 h at 80° C. After cooling to rt, the reaction was filtered using MeOH to remove the potassium phosphate and then concentrated in vacuo. The crude product was purified by reverse phase prep HPLC and the appropriate fractions were concentrated in vacuo to remove MeOH. The resulting aqueous layer was made basic with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (20 mg, 26%) as a white solid. 1H NMR (CD3OD) δ 7.84-7.94 (m, 2H), 7.44-7.41 (m, 1H), 7.34-7.19 (m, 3H), 6.92 (t, 1H, J=8.8 Hz), 6.87 (d, 1H, J=2.8 Hz), 6.50 (dd, 1H, J=12.4, 2.4 Hz), 6.46-6.43 (m, 1H), 2.04 (s, 3H); MS(ESI+) m/z 378.3 (M+H)+.

Aufarbeitung

  1. customThe flask was flushed with nitrogen
  2. additiont-BuOH was added (0.40 mL)
  3. temperatureAfter cooling to rt
  4. filtrationthe reaction was filtered
  5. customto remove the potassium phosphate
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by reverse phase prep HPLC
  8. concentrationthe appropriate fractions were concentrated in vacuo
  9. customto remove MeOH
  10. extractionextracted with ethyl acetate
  11. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  12. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-7968bd195bd64eb0b1229e3cd9d127bc
Quelldatensatz
uspto-grants-2008_10
Patentnummer
US07439246B2

Notizen zur Reaktion

Wird geladen…