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

HRID 473128Notes

Reaction equation

HRID 473128 reaction equation
[F:1][C:2]([F:21])([C:14]1[CH: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.[I-].[K+]>CN(C=O)C.C(O)(=O)C>[F:1][C:2]([F:21])([C:14]1[CH: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

8

Reactant 5

HCID 4875Potassium IodideHCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517775HCID 178517775, compound

Product 1

HCID 568485582-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amineYield 35%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (200 mg, 0.68 mmol) was added phosphorous oxychloride (4 mL) and the mixture was heated at 90° C. for 1 h. The mixture was concentrated and toluene (4 mL) was added and evaporated. This crude material was partitioned between EtOAc and a saturated sodium bicarbonate solution and the organic layer was dried over sodium sulfate and concentrated to afford a yellow solid. To this solid was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1.03 mmol), DIEA (0.18 mL, 1.54 mmol), and potassium iodide (113 mg, 1.03 mmol) in DMF (4 mL) and the mixture was stirred at rt overnight. Acetic acid (0.2 mL) was added and the 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)quinazolin-4-amine (88 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 5.99 (s, 1H), 7.65 (t, 1H), 7.83-7.94 (m, 2H), 7.97-8.07 (m, 2H), 8.58-8.78 (m, 2H), 10.70 (s, 1H), 12.18 (bs, 1H); LC-MS (ESI) m/z 371 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated
  2. additiontoluene (4 mL) was added
  3. customevaporated
  4. customThis crude material was partitioned between EtOAc
  5. dry with materiala saturated sodium bicarbonate solution and the organic layer was dried over sodium sulfate
  6. concentrationconcentrated
  7. customto afford a yellow solid
  8. customthe mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
  9. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-a372260ca4c14cc6b2134f2422808d52
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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