Phosphorus oxybromide → HCID 56848812, compound

HRID 473203Notes

Reaction equation

HRID 473203 reaction equation
[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11]([NH:44][C:41]2[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=2)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

Participants

7

Reactant 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178488826HCID 178488826, compound

Product 1

HCID 56848812HCID 56848812, compoundYield 30.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
105 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxyquinazolin-4-ol (450 mg, 1.4 mmol) were added phosphoryl tribromide (3.14 g) and toluene (4 mL) followed by DIEA (0.488 mL, 2.8 mmol). The mixture was heated at 105° C. for 1 h. 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 residue was added a solution of 5-methyl-1H-pyrazol-3-amine (300 mg, 3.1 mmol) in DMF (4 mL) and the mixture was stirred at rt for 3 days. The crude mixture was purified by preparative HPLC (Varian C-18 reverse phase column, eluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (170 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 3.95 (s, 3H) 5.91 (s, 1H) 7.38 (d, J=7.91 Hz, 1H) 7.56 (t, J=8.10 Hz, 1H) 7.93-8.06 (m, 2H) 8.19 (d, J=8.10 Hz, 1H) 8.66 (s, 1H) 10.53 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 401 (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 C-18 reverse phase column
  6. washeluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN)

Sources & evidence

ORD record
ord-f2d5bdb1c36e4cad8ae0cc5dd02ea70e
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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