Diisopropylethylamine → 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea

HRID 871430Notes

Reaction equation

HRID 871430 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)C(C)C)(C)C.[C:32]1([C:38]2[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C3C=CC=CC=3)[CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:44]([NH:43][C:40]2[CH:39]=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:42][N:41]=2)=[O:45])[CH:20]=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 498410023-[(6,7-Dimethoxy-4-quinazolinyl)oxy]anilineHCID 59394374Phenyl 5-phenylisoxazol-3-ylcarbamate

Product 1

HCID 569538691-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)ureaYield 32%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol), in tetrahydrofuran (1.5 mL) was treated with N,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from the previous step (126 mg, 0.45 mmol). The reaction mixture was heated to 50° C. for 2.5 h. After cooling to room temperature, the mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with dichloromethane and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (47.16 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 7.86 (d, 2H), 7.87-7.51 (m, 4H), 7.51-7.40 (m, 2H), 7.31-7.21 (m, 3H), 7.00 (d, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484 (M+H)+.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe mixture was partitioned between dichloromethane
  3. extractionThe water phase was back extracted three times with dichloromethane
  4. dry with materialdried (MgSO4)
  5. concentrationConcentration under reduced pressure
  6. customgave a residue which
  7. customwas purified by preparative HPLC (phenylhexyl reverse phase column)
  8. customThe obtained solid was triturated with anhydrous diethyl ether

Sources & evidence

ORD record
ord-de3d40f2cee74c9ea85b14ebd65fed6e
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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