[5-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-isoxazol-3-yl]-carbamic acid phenyl ester → 1-(3-(7-Hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

HRID 631583Notes

Reaction equation

HRID 631583 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.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=4)=[O:34])[CH:21]=[CH:20][CH:19]=3)=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]

Participants

4

Reactant 2

HCID 66877298[5-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-isoxazol-3-yl]-carbamic acid phenyl ester2×HCID 1363377714-(3-Aminophenoxy)-6-methoxyquinazolin-7-ol

Product 1

HCID 1360737511-(3-(7-Hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaYield 23%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (100 mg, 0.35 mmol) prepared as described in example 95A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (111 mg, 0.35 mmol) and the mixture was heated to 60° C. for 2 h. Additional phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg, 0.16 mmol) was added and heating was continued for a further 72 h. Concentration in vacuo followed by purification via preparative reverse phase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O), afforded 1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (40 mg, 23%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.93 (brs, 1H), 9.83 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 7.56 (dd, J=2.1, 2.1 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.26 (dd, J=8.1, 8.1 Hz, 1H), 7.21 (s, 1H), 6.96 (m, 1H), 6.88 (s, 1H), 3.98 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.

Workup

  1. temperatureheating
  2. concentrationConcentration in vacuo
  3. customfollowed by purification via preparative reverse phase HPLC (
  4. washeluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O),

Sources & evidence

ORD record
ord-97ab415906b54f4194f4a9170ff635a1
Source dataset
uspto-grants-2016_04
Patent number
US09320739B2

Reaction notes

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