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

HRID 871667Notes

Reaction equation

HRID 871667 reaction equation
[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][C:42]=1[F:43]

Participants

4

Reactant 2

HCID 668768273-(6,7-Dimethoxyquinazolin-4-yloxy)-4-fluoroanilineHCID 668775214-Chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate

Product 1

HCID 582678951-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)ureaYield 64%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (170 mg, 0.571 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (prepared as described in Example 266A steps 1 and 2) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.44 (brs, 1H), 9.08 (brs, 1H), 8.58 (s, 1H), 7.69 (m, 1H), 7.59 (s, 1H), 7.35-7.42 (m, 3H), 6.14 (s, 1H), 4.00 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto give the crude product
  3. customPurification via silica gel flash chromatography (
  4. washeluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-c96a28879d064ae0ab1330afa119dff1
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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