m-Chloroperbenzoic acid → 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 473168Notes

Reaction equation

HRID 473168 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](SC)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[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:41][C:38]2[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=2)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1

Participants

6

Reactant 3

HCID 70297m-Chloroperbenzoic acidHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 666103932-(Difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline

Product 1

HCID 568486902-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amineYield 36%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline (152 mg, 0.454 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (168 mg, 0.681 mmol), and the mixture was stirred for 40 min at 0° C. DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4, and concentrated under reduced pressure. To the residue (154 mg) was added 5-methyl-1H-pyrazol-3-amine (132 mg, 1.36 mmol) in THF (4 mL), and the mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Varian Diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/5% ACN/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (62.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 12.08-12.20 (m, 1H), 10.53-10.66 (m, 1H), 8.66 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 7.93-8.03 (m, 2H), 7.66 (s, 1H), 7.48 (d, J=7.5 Hz, 1H), 5.99 (s, 1H), 2.51 (s, 4H), 2.18 (s, 3H). LCMS (ESI) m/z 386 (M+H)+.

Workup

  1. washthe mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL)
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated under reduced pressure
  4. stirringthe mixture was stirred at rt overnight
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by reverse phase HPLC (Varian Diphenyl reverse phase column
  7. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/5% ACN/H2O)

Sources & evidence

ORD record
ord-5a0117c602874f8f966c5a43bdf770e0
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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