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

HRID 473183
Notes
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Reaction equation

HRID 473183 reaction equation
[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:41][C:42]1[NH:46][N:45]=[C:44]([NH2:47])[CH:43]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:47][C:44]2[CH:43]=[C:42]([CH3:41])[NH:46][N:45]=2)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517777HCID 178517777, compound

Product 1

HCID 568486942-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amineYield 33.3%

Reagents, catalysts & solvents

2
HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
105 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (250 mg, 0.66 mmol) was added phosphoryl tribromide (2.3 g) and toluene (2 mL) followed by DIEA (0.232 mL, 1.33 mmol). The mixture was heated at 105° C. for 0.5 h, then allowed to cool to rt. The mixture partitioned between EtOAc and saturated aq sodium bicarbonate and 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 (280 mg, 2.8 mmol) in DMF (5 mL) and the mixture was stirred at rt for 2 h. 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 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amine (100 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.02 (s, 1H) 7.71 (t, J=8.10 Hz, 1H) 7.86-8.10 (m, 3H) 8.60-8.79 (m, 2H) 10.95 (s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 455 (M+H)+.

Workup

  1. temperatureto cool to rt
  2. customThe mixture 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-cd3005308fa94a35a823991083b9c0d6
Source dataset
uspto-grants-2014_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08633207B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes