Diisopropylethylamine → 1-(3-(6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea

HRID 1917972Notes

Reaction equation

HRID 1917972 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(CC)C(C)C)(C)C.[C:35]1([C:41]2[O:45][N:44]=[C:43]([NH:46][C:47](=O)[O:48]C3C=CC=CC=3)[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.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][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:47]([NH:46][C:43]2[CH:42]=[C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:45][N:44]=2)=[O:48])[CH:23]=[CH:24][CH:25]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 59394374Phenyl 5-phenylisoxazol-3-ylcarbamateHCID 668758053-(6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline

Product 1

HCID 582679091-(3-(6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)ureaYield 70%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

According to the procedure described in Example 113C, 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) in THF (1.5 mL) was treated with N,N-diisopropylethylamine (68 μl, 0.39 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from Example 113B (109 mg, 0.39 mmol). The reaction mixture was heated to 50° C. for 4 h. After cooling to room temperature, the mixture was partitioned between chloroform and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with chloroform 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-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (110 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 7.86 (d, 2H), 7.62-7.53 (m, 5H), 7.51 (t, 2H), 7.28 (m, 2H), 6.99 (d, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe mixture was partitioned between chloroform
  3. extractionThe water phase was back extracted three times with chloroform
  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-28b306467a3a43e69169c4fa98ca5a9f
Source dataset
uspto-grants-2013_12
Patent number
US08618289B2

Reaction notes

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