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

HRID 1801902Notes

Reaction equation

HRID 1801902 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-bab096973e4340869f10576774ee64f5
Source dataset
uspto-grants-2013_01
Patent number
US08349851B2

Reaction notes

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