Phosphorus oxybromide → HCID 56848757, compound

HRID 473192Notes

Reaction equation

HRID 473192 reaction equation
[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[CH:6][C:7]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1

Participants

7

Reactant 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178504655HCID 178504655, compound

Product 1

HCID 56848757HCID 56848757, compoundYield 45%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-(methylsulfonyl)quinazolin-4-ol (76 mg, 0.21 mmol) were added phosphoryl tribromide (1.21 g), toluene (0.5 mL), and DIEA (0.072 mL, 0.42 mmol), and the mixture was heated at 100° C. for 10 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. 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 (59 mg, 0.6 mmol) in DMF (3 mL) and the mixture was stirred at rt for 20 min. The crude mixture was purified by preparative HPLC (Phenomenex C-18 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)-7-(methylsulfonyl)quinazolin-4-amine (40 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 3.39 (s, 3H) 6.06 (s, 1H) 7.97-8.05 (m, 2H) 8.09 (d, J=7.72 Hz, 1H) 8.33 (s, 1H) 8.67 (s, 1H) 8.97 (d, J=8.48 Hz, 1H) 11.10 (br s, 1H) 12.28 (br s, 1H); LC-MS (ESI) m/z 449 (M+H)+.

Workup

  1. temperatureThe mixture was cooled
  2. custompartitioned 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 (Phenomenex C-18 reverse phase column
  6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-fcc5d5d8f8a24b399df56f32f66430fc
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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