Cesium carbonate → N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide

HRID 1020377Notes

Reaction equation

HRID 1020377 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH:44]=[CH2:45]>C(#N)C>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:46])[CH2:44][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 3677416N-(2-fluorophenyl)acrylamide2×HCID 67391262N-(1H-indol-5-yl)-2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolecarboxamide

Product 1

HCID 57461810N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamideYield 7.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of compound 44 (0.080 g, 0.204 mmol) and cesium carbonate (0.133 g, 0.408 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature was added N-(2-fluorophenyl)acrylamide (C-4) (0.101 g, 0.612 mmol) in one portion. The reaction mixture was stirred at room temperature for 30 h, then additional N-(2-fluorophenyl)acrylamide (C-4) (0.168 g, 1.02 mmol) was added, and the reaction mixture was heated at 50° C. for 24 h. The reaction mixture was filtered over a celite pad, washed with methylene chloride (50 mL) and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (H2O:CH3CN eluant gradient) gave 8.7 mg (6.8% yield) of N-[1-(3-(2-fluorophenylamino)-3-oxopropyl)-1H-indol-5-yl]-2-(3-methylpiperidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxamide (71) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (br s, 1H), 10.05 (br s, 1H), 9.82 (br s, 1H), 7.88 (m, 1H), 7.85 (m, 1H), 7.53 (d, 1H, J=9.1 Hz), 7.37 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.42 (m, 1H), 4.49 (br t, 2H, J=6.6 Hz), 4.12 (m, 2H), 3.05 (t, 1H, J=11.5 Hz), 2.92 (t, 2H, J=6.6 Hz), 2.74 (t, 1H, J=11.9 Hz), 1.78 (m, 3H), 1.54 (m, 1H), 1.16 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 558.

Workup

  1. temperaturethe reaction mixture was heated at 50° C. for 24 h
  2. filtrationThe reaction mixture was filtered over a celite pad
  3. washwashed with methylene chloride (50 mL)
  4. concentrationconcentrated
  5. customPurification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc)

Sources & evidence

ORD record
ord-8d9a581f579f487e9c3d94f61b862df7
Source dataset
uspto-grants-2014_05
Patent number
US08716312B2

Reaction notes

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