Sodium Thiosulfate → 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)morpholin-3-one

HRID 473201Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 473201
[F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:53][C:54]1[NH:58][N:57]=[C:56]([NH2:59])[CH:55]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11]([NH:59][C:56]2[CH:55]=[C:54]([CH3:53])[NH:58][N:57]=2)[C:10]2[C:5](=[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

Komponenten

8

Edukt 5

HCID 24477Sodium ThiosulfateHCID 70297m-Chloroperbenzoic acidHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 516892Sodium BicarbonateHCID 666104604-(2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one

Produkt 1

HCID 568488114-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)morpholin-3-oneAusbeute 20 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittel2×HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

To 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one (180 mg, 0.428 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 158 mg, 0.64 mmol) and the mixture was stirred for 30 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by saturated aq sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (3 mL) and 5-methyl-1H-pyrazol-3-amine (124 mg, 1.28 mmol) and the mixture was stirred at rt for 5 min. A precipitate formed which was collected by filtration and then purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)morpholin-3-one (40 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.65 (d, J=4.52 Hz, 2H) 3.85-3.93 (m, 2H) 4.18 (s, 2H) 6.20 (s, 1H) 7.63-7.71 (m, 1H) 7.82 (d, J=7.16 Hz, 1H) 7.93-8.05 (m, 2H) 8.57-8.73 (m, 2H) 10.84 (br s, 1H) 12.24 (br s, 1H); LC-MS (ESI) m/z 470 (M+H)+.

Aufarbeitung

  1. customThe organic layer was separated
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated under reduced pressure
  4. stirringthe mixture was stirred at rt for 5 min
  5. customA precipitate formed which
  6. filtrationwas collected by filtration
  7. custompurified by preparative HPLC (Varian C-18 reverse phase column
  8. washeluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O)

Quellen und Nachweise

ORD-Eintrag
ord-70d6d46fc9de46ee8b9921e606c1ca31
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08633207B2

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