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

HRID 473215Notes

Reaction equation

HRID 473215 reaction equation
[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.O.C1(C)C=CC=CC=1>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[C:10]2[C:5](=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

Participants

8

Reactant 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 1785265332-[difluoro-(5-fluoro-2-pyridinyl)methyl]-8-nitro-1H-quinazolin-4-one

Product 1

HCID 568488682-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-nitroquinazolin-4-amine

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-nitroquinazolin-4-ol (312 mg, 0.92 mmol) were added phosphoryl tribromide (1.66 g), toluene (3 mL), and DIEA (0.325 mL, 1.85 mmol), and the mixture was heated at 90° C. for 0.75 h. The mixture was allowed to cool and was partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (220 mg, 2.3 mmol) in DMF (4 mL) and the mixture was stirred at rt for 0.5 h. Water was added and the resulting precipitate was collected by filtration and dried on the funnel to give a crude solid (406 mg, quantitative). An analytical sample was prepared by purification with 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-nitroquinazolin-4-amine. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.95 (s, 1H) 7.78 (t, J=8.01 Hz, 1H) 7.95-8.07 (m, 2H) 8.38 (d, J=7.54 Hz, 1H) 8.67 (s, 1H) 8.94 (d, J=8.10 Hz, 1H) 11.18 (br s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 416 (M+H)+.

Workup

  1. temperatureto cool
  2. customwas partitioned between EtOAc
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. concentrationconcentrated
  5. filtrationthe resulting precipitate was collected by filtration
  6. customdried on the funnel
  7. customto give a crude solid (406 mg, quantitative)
  8. customAn analytical sample was prepared by purification with preparative HPLC (Varian diphenyl reverse phase column
  9. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-4d19b894141d498eb38582a14835069a
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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