3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluoroaniline → 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

HRID 871638Notes

Reaction equation

HRID 871638 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[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27].FC(F)(F)C(C1ON=C(NC(=O)[O-])C=1)(C)C>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][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:23])=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 178195183-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluoroanilineHCID 66877298[5-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-isoxazol-3-yl]-carbamic acid phenyl esterHCID 866535255-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate

Product 1

HCID 582677891-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaYield 54%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline from the previous step (150 mg, 0.476 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (224 mg, 0.714 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. An additional amount of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg, 0.159 mmol) was added, and stirred for an additional 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (137 mg, 54%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.01 (brs, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 8.07 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 6.91 (s, 1H), 4.00 (s, 6H), 1.56 (s, 6H); LC-MS (ESI) m/z 536 (M+H)+.

Workup

  1. stirringstirred for an additional 15 h
  2. concentrationConcentration in vacuo
  3. customfollowed by purification via silica gel column chromatography (
  4. washeluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate),

Sources & evidence

ORD record
ord-4e996be258704a19b3b67699809402bf
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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