Water → 1-(5-Tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea

HRID 1918050Notes

Reaction equation

HRID 1918050 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:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].CCN(C(C)C)C(C)C.[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C2C=CC=CC=2)[CH:39]=1)([CH3:37])([CH3:36])[CH3:35].O>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44]([NH:21][C:20]2[CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]([F:24])=[CH:18][C:19]=2[F:23])=[O:45])[CH:39]=1)([CH3:37])([CH3:35])[CH3:36]

Participants

7

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 13489605Phenyl 5-tert-butylisoxazol-3-ylcarbamateHCID 668767545-(6,7-Dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline

Product 1

HCID 566652481-(5-Tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)ureaYield 25.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmol) in THF (10 mL), DIEA (58 mg, 0.45 mmol), DMAP (20 mg, 0.16 mmol), and phenyl 5-tert-butylisoxazol-3-ylcarbamate (117 mg, 0.32 mmol) were added and the mixture heated overnight at 70° C. The mixture was poured into water and extracted with EtOAc three times. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel chromatography eluting with EtOAc/Hexane (3-80%). The appropriate fractions were concentrated to afford 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea (37.56 mg, 25% yield). 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 9H), 4.05 (s, 6H), 6.09 (s, 1H), 6.85 (s, 1H), 7.28 (s, 1H), 7.35 (s, 1H), 8.28 (m, 1H), 8.70 (s, 1H), 9.50 (s, 1H). LC-MS (ESI) m/z 500 (M+H)+

Workup

  1. extractionextracted with EtOAc three times
  2. dry with materialThe extracts were dried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified
  6. washeluting with EtOAc/Hexane (3-80%)
  7. concentrationThe appropriate fractions were concentrated

Sources & evidence

ORD record
ord-64b0b2b848c44ff3ac995a9be31d6c4c
Source dataset
uspto-grants-2013_12
Patent number
US08618289B2

Reaction notes

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