Phosphorus oxybromide → HCID 56848759, compound

HRID 473197Notes

Reaction equation

HRID 473197 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2O.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[NH:43][C:40]1[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=1

Participants

7

Reactant 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517779HCID 178517779, compound

Product 1

HCID 56848759HCID 56848759, compoundYield 30.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
105 °C

Procedure

To 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (200 mg, 0.61 mmol) were added phosphoryl tribromide (1.2 g) and toluene (2 mL) followed by DIEA (0.214 mL, 1.22 mmol). The mixture was heated at 105° C. for 45 min. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the crude residue was added a solution of 5-methyl-1H-pyrazol-3-amine (137 mg, 1.41 mmol) in DMF (4 mL) and the mixture was stirred at rt for 45 min. 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 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (75 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 5.91 (s, 1H) 7.63 (t, J=8.01 Hz, 1H) 8.07 (d, J=7.54 Hz, 1H) 8.67 (d, J=8.29 Hz, 1H) 9.14 (s, 2H) 10.91 (br s, 1H) 12.24 (br s, 1H); LC-MS (ESI) m/z 406 (M+H)+.

Workup

  1. temperatureto cool
  2. customwas 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)

Sources & evidence

ORD record
ord-73f6739554884465b22955d82e8b3dac
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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