4-(3-Aminophenoxy)-7-methoxyquinazolin-6-ol → 1-(3-(6-Hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

HRID 631584Notes

Reaction equation

[NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:17][CH3:18])[N:9]=[CH:8][N:7]=[C:6]2[O:5][C:4]1[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=2)=[O:34])[CH:21]=[CH:20][CH:19]=1

Participants

Conditions

Temperature: 60 °C

Procedure

To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (70 mg, 0.247 mmol) described in Example 107A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (90 mg, 0.287 mmol) and the mixture was heated to 60° C. for 15 h. Concentration in vacuo followed by trituration of the resulting solid with methanol afforded, after filtration and drying, 1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (73 mg, 59%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.75 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 7.55 (dd, J=2.1, 2.1 Hz, 1H), 7.50 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (dd, J=9, 1.2 Hz, 1H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.88 (s, 1H), 4.00 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.

Workup

concentrationConcentration in vacuo
customafforded
filtrationafter filtration
customdrying

Sources & evidence

ORD record: ord-ea3e38eda57d47a08cf821510c6aea12
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09320739B2

Reaction notes

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