Diisopropylethylamine → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-difluoromethoxy-phenyl)-amide

HRID 657231

Reaktionsgleichung

Reaktionsgleichung von HRID 657231
[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[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[F:24][CH:25]([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:24][CH:25]([F:34])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([N:18]2[CH2:19][CH2:20][CH: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)[CH2:16][CH2:17]2)=[O:22])=[CH:32][CH:33]=1

Komponenten

5

Edukt 3

HCID 81531DiisopropylethylamineHCID 7373634-(Difluoromethoxy)anilineHCID 587707144-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride

Produkt 1

HCID 587707164-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-difluoromethoxy-phenyl)-amideAusbeute 32 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added 4-(difluoromethoxy)aniline (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100° C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).

Aufarbeitung

  1. temperatureit was cooled to room temperature
  2. custompartitioned between EtOAc and water
  3. dry with materialThe combined EtOAc extracts were dried (Na2SO4)
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent)

Quellen und Nachweise

ORD-Eintrag
ord-4c43b9a196ce4f3f856351e7c02a74b6
Quelldatensatz
uspto-grants-2011_12
Patentnummer
US08071768B2

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