Phosphorus oxychloride → HCID 56848559, compound

HRID 473133Notes

Reaction equation

HRID 473133 reaction equation
[F:1][C:2]([F:21])([C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)(Cl)=O.[CH3:27][C:28]1[NH:32][N:31]=[C:30]([NH2:33])[CH:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC(O)=O>[F:1][C:2]([F:21])([C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11]([NH:33][C:30]2[CH:29]=[C:28]([CH3:27])[NH:32][N:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1

Participants

7

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517778HCID 178517778, compound

Product 1

HCID 56848559HCID 56848559, compoundYield 33.1%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

To 2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (190 mg, 0.65 mmol) was added phosphorous oxychloride (4 mL) and the mixture was heated at 95° C. for 2 h. The mixture was concentrated under reduced pressure, toluene was added, and the solution was again concentrated under reduced pressure. The residue was diluted with EtOAc and washed with saturated aq NaHCO3. 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 (72 mg, 0.74 mmol), DIEA (0.14 mL, 0.78 mmol), and KI (40 mg, 0.24 mmol) in DMF (4 mL) and the mixture was stirred at rt overnight. AcOH (0.2 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyrimidin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (80 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 12.19 (br s, 1H), 10.72 (s, 1H), 9.13 (s, 2H), 8.70 (d, J=8.1 Hz, 1H), 7.78-8.01 (m, 2H), 7.66 (t, J=7.3 Hz, 1H), 5.94 (s, 1H), 2.18 (s, 3H); LC-MS (ESI) m/z 372 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated under reduced pressure, toluene
  2. additionwas added
  3. concentrationthe solution was again concentrated under reduced pressure
  4. additionThe residue was diluted with EtOAc
  5. washwashed with saturated aq NaHCO3
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customthe mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
  9. washeluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=0.05% AcOH/H2O)

Sources & evidence

ORD record
ord-832228e1736545158aa2b04501debfb0
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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