Hydrochloric Acid → 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine

HRID 1864331Notes

Reaction equation

[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH2:5].Cl.O1CCOCC1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:35])[N:28]=[CH:27][N:26]=1>C(#N)C>[F:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[C:25]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:2]([CH3:1])[CH:3]=1)=[N:26][CH:27]=[N:28]2

Participants

Conditions

Temperature: 80 °C

Procedure

3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5-fluoroquinazoline (5 g, 27.5 mmol; obtained as described in PCT Int. Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80° C. for 2 hours. After cooling, the precipitate washed with acetonitrile. This precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer washed with brine and dried over MgSO4. Evaporation of the solvents gave 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum (CDCl3); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H).

Workup

temperatureAfter cooling
washthe precipitate washed with acetonitrile
customThis precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate
washThe organic layer washed with brine
dry with materialdried over MgSO4
customEvaporation of the solvents

Sources & evidence

ORD record: ord-b8cfda61f7eb49d0a5b7d5dacbe3638d
Source dataset: uspto-grants-2009_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07625908B2

Reaction notes

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