Potassium Iodide → 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 625755Notes

Reaction equation

HRID 625755 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[NH:39][N:38]=[C:37]([NH2:40])[CH:36]=1>CN(C=O)C.O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]1[N:3]=[C:2]([NH:40][C:37]2[CH:36]=[C:35]([CH3:34])[NH:39][N:38]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 729429294-Chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline

Product 1

HCID 468926232-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amineYield 19%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-fluoroquinazoline (0.160 g, 0.492 mmol) in DMF (2 mL) at rt were added potassium iodide (0.082 g, 0.492 mmol), DIEA (0.094 mL, 0.541 mmol) and 5-methyl-1H-pyrazol-3-amine (0.048 g, 0.492 mmol). After stirring the reaction mixture at 50° C. overnight, the mixture was cooled to rt and H2O (15 mL) was added. The precipitate was collected by filtration and washed with H2O. The crude product was purified on HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(4-fluorophenyl)methyl)-7-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a white powder (36 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H), 6.27 (s, 1H), 7.35 (t, 2H), 7.56 (m, 1H), 7.72-763 (m, 3H), 8.78 (m, 1H), 10.82 (s, 1H), 12.23 (s, 1H); LC-MS (ESI) m/z 388 (M+H)+.

Workup

  1. temperaturethe mixture was cooled to rt
  2. filtrationThe precipitate was collected by filtration
  3. washwashed with H2O
  4. customThe crude product was purified on HPLC (Phenomenex phenylhexyl reverse phase column
  5. washeluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-7ec10f5fd85f43f180747201ff49c0ac
Source dataset
uspto-grants-2016_04
Patent number
US09308207B2

Reaction notes

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