Diisopropylethylamine → 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea

HRID 631402노트

반응식

HRID 631402 반응식
[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[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[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[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[O:28][N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1

참가 물질

6

반응물 3

HCID 81531DiisopropylethylamineHCID 13489689Phenyl 3-isopropylisoxazol-5-ylcarbamateHCID 498410023-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline

생성물 1

HCID 442434351-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea수율 19%

시약·촉매·용매 2

HCID 142844-(Dimethylamino)pyridine촉매HCID 8028Tetrahydrofuran용매

실험 절차

A stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.30 mmol), phenyl 3-isopropylisoxazol-5-ylcarbamate from the previous step (89 mg, 0.36 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol) and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) in dry tetrahydrofuran (1.5 mL), was heated at 50° C. for 30 mins. After cooling to room temperature, concentration under reduced pressure gave a residue which was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (using phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea as a colorless solid (25 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ 10.30 (brs, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.39-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.00 (s, 6H), 2.90 (septet, J=6 Hz, 1H), 1.19 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 450 (M+H)+.

후처리

  1. concentrationconcentration under reduced pressure
  2. customgave a residue which
  3. customwas partitioned between water (50 mL) and dichloromethane (50 mL)
  4. customThe organic layer was separated
  5. washwashed with brine (50 mL)
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by preparative HPLC (
  9. washeluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O)

출처 및 근거

ORD 기록
ord-d8877972e39448edaefb7d64957de0d8
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09320739B2

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