Piperidine → N-{3-[3-Cyclohexyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide

HRID 24363Notes

Reaction equation

HRID 24363 reaction equation
[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33](=[O:37])[NH:34]2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].N1CCCCC1>C(O)C.C(OCC)(=O)C>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=[C:32]2[C:31]3[C:35](=[CH:36][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[NH:34][C:33]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 8082PiperidineHCID 2749839N-(2-Oxoindolin-6-yl)acetamideHCID 542261743-Cyclohexyl-4-morpholinoethoxybenzaldehyde

Product 1

HCID 53981954N-{3-[3-Cyclohexyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamideYield 34.6%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3-cyclohexyl-4-morpholinoethoxybenzaldehyde (3 g, 9.45 mmol), 6-acetamido-2-oxindole (3.5 g, 18.9 mmol) and piperidine (5 ml, 50 mmol) in ethanol (35 ml) was held in a sealed tube at 100° C. for 6 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 ml) and filtered to remove excess 6-acetamido-2-oxindole. The filtrate was extracted with 0.5N hydrochloric acid (200 ml) and brine (2×200 ml). The acid wash was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with brine (200 ml), dried over magnesium sulfate and concentrated. The combined solids were dissolved in dichloromethane (25 ml) and precipitated with diethyl ether (500 ml) to afford 1.6 g of a mustard yellow solid. The solid was dissolved in methanol (100 ml) and filtered, affording a yellow solid (which was set aside) and then precipitated with water (400 ml) and filtered. The solid residue was redissolved in methanol and concentrated to a solid. This process was repeated twice to afford ˜82% pure isomer 1 by HPLC. The filtered yellow solid was 77% isomer 2 by HPLC.

Workup

  1. temperatureThe reaction mixture was cooled
  2. filtrationfiltered
  3. customto remove excess 6-acetamido-2-oxindole
  4. extractionThe filtrate was extracted with 0.5N hydrochloric acid (200 ml) and brine (2×200 ml)
  5. washThe acid wash
  6. extractionextracted with ethyl acetate (2×200 ml)
  7. washThe combined organic layers were washed with brine (200 ml)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. dissolutionThe combined solids were dissolved in dichloromethane (25 ml)
  11. customprecipitated with diethyl ether (500 ml)

Sources & evidence

ORD record
ord-6e173cd0ab92490eb063038c97dd05c3
Source dataset
uspto-grants-2005_02
Patent number
US06855730B2

Reaction notes

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