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

HRID 657231

Reaction equation

HRID 657231 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[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

Participants

5

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

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+).

Workup

  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)

Sources & evidence

ORD record
ord-4c43b9a196ce4f3f856351e7c02a74b6
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Linked notes

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