Pyridine → 5-Chloro-3-(2,4-dimethoxyphenyl)-3-(4-pyridin-4-ylpiperazin-1-yl)-1,3-dihydroindol-2-one

HRID 449799Notes

Reaction equation

HRID 449799 reaction equation
N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])O.[N:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.ClC1C2C(=CC=CC=2)NC1=O>ClCCl.CN(C)C=O.O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[N:42]1[CH2:43][CH2:44][N:39]([C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[CH2:40][CH2:41]1

Participants

9

Reactant 5

HCID 1049PyridineHCID 24386Thionyl ChlorideHCID 705171-(4-Pyridyl)piperazineHCID 124185093-Chloro-1,3-dihydro-2H-indol-2-oneHCID 219059025-Chloro-3-(2,4-dimethoxyphenyl)-3-hydroxy-1,3-dihydroindol-2-one

Product 1

HCID 684279685-Chloro-3-(2,4-dimethoxyphenyl)-3-(4-pyridin-4-ylpiperazin-1-yl)-1,3-dihydroindol-2-oneYield 22.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Pyridine (1.51 mL, 18.76 mmol) and thionyl chloride (1.03 mL, 14.07 mmol) were added to a solution of 5-chloro-3-(2,4-dimethoxyphenyl)-3-hydroxy-1,3-dihydroindol-2-one (prepared as described in WO 2005/030755, 3.00 g, 9.38 mmol) in dichloromethane (70 mL) while cooling in ice. The reaction mixture was then stirred at 0° C. for 1 hour. While stirring, water was added to the reaction mixture, and it was then extracted with dichloromethane. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. 1-Pyridin-4-yl-piperazine (2.17 g, 13.31 mmol) was added to a solution of the 3-chloro-oxindole intermediate obtained in this way in dimethylformamide (25 mL), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted again with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure, resulting in 1.00 g of the title compound which was employed without further purification in the next step.

Workup

  1. temperaturewhile cooling in ice
  2. stirringWhile stirring
  3. extractionwas then extracted with dichloromethane
  4. washThe organic phase was washed with water and saturated brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. stirringthe reaction mixture was stirred at room temperature for 12 h
  8. concentrationThe reaction mixture was concentrated under reduced pressure
  9. customthe residue was partitioned between ethyl acetate and water
  10. extractionThe aqueous phase was extracted again with ethyl acetate
  11. dry with materialThe combined organic phase was dried over sodium sulfate
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b4b70e19a48e4d5985e5a3ae54cee7e9
Source dataset
uspto-grants-2013_07
Patent number
US08486931B2

Reaction notes

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