Phenyl 5-tert-butylisoxazol-3-ylcarbamate → 1-(5-Tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea

HRID 631357Notes

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

Participants

Conditions

Temperature: 60 °C

Procedure

A stirred mixture of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol from the previous step (500 mg, 1.77 mmol) and phenyl 5-tert-butylisoxazol-3-ylcarbamate (460 mg, 1.77 mmol) in dry N,N-dimethylformamide (10 mL) was heated at 60° C. for 5 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered and dried under reduced pressure to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea as a cream solid (650 mg, 82%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.78 (brs, 1H), 9.58 (brs, 1H), 9.00 (brs, 1H), 8.48 (s, 1H), 7.55-7.57 (m, 2H), 7.40 (m, 1H), 7.24-7.26 (m, 2H), 6.97 (m, 1H), 6.48 (s, 1H), 3.99 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.

Workup

temperatureAfter cooling to room temperature the mixture
concentrationwas concentrated under reduced pressure
customThe residue was triturated with diethyl ether
filtrationfiltered
customdried under reduced pressure

Sources & evidence

ORD record: ord-ac86e92424f0438bb5aeb87ac7f51666
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09320739B2

Reaction notes

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