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Phosphorus oxybromide → 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amine

HRID 473183
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 473183
[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:41][C:42]1[NH:46][N:45]=[C:44]([NH2:47])[CH:43]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:47][C:44]2[CH:43]=[C:42]([CH3:41])[NH:46][N:45]=2)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517777HCID 178517777, Verbindung

Produkt 1

HCID 568486942-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amineAusbeute 33,3 %

Reagenzien, Katalysatoren, Lösungsmittel

2
HCID 1140TolueneLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
105 °C

Versuchsvorschrift

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (250 mg, 0.66 mmol) was added phosphoryl tribromide (2.3 g) and toluene (2 mL) followed by DIEA (0.232 mL, 1.33 mmol). The mixture was heated at 105° C. for 0.5 h, then allowed to cool to rt. The mixture partitioned between EtOAc and saturated aq sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (280 mg, 2.8 mmol) in DMF (5 mL) and the mixture was stirred at rt for 2 h. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amine (100 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.02 (s, 1H) 7.71 (t, J=8.10 Hz, 1H) 7.86-8.10 (m, 3H) 8.60-8.79 (m, 2H) 10.95 (s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 455 (M+H)+.

Aufarbeitung

  1. temperatureto cool to rt
  2. customThe mixture partitioned between EtOAc and saturated aq sodium bicarbonate
  3. dry with materialthe organic layer was dried over sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
  6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

Quellen und Nachweise

ORD-Eintrag
ord-cd3005308fa94a35a823991083b9c0d6
Quelldatensatz
uspto-grants-2014_01
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08633207B2

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