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

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Reaction Conditions

Reaction Steps

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)+.

Provenance & Evidence