Sodium hydride → Cis(+/-)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one

HRID 255334Notes

Reaction equation

HRID 255334 reaction equation
[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:25]([O:44][CH3:45])[CH2:24]1)(=O)=O>CN(C=O)C>[CH2:37]([N:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:24][C@H:25]1[O:44][CH3:45])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 642082495,7-Difluoro-1,2-dihydroquinolin-2-one2×HCID 86642652Cis(+/-)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl methanesulfonate

Product 1

HCID 86642651Cis(+/-)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-oneYield 27%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

A solution of 5,7-difluoroquinolin-2(1H)-one (Intermediate 25, 300 mg, 1.70 mmol) in dry DMF (10 mL) was treated with sodium hydride (60% in oil, 80 mg, 2.00 mmol) with cooling in an ice bath. The reaction was stirred at room temperature for 90 min. The reaction was again cooled in an ice bath and treated with a solution of cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl methanesulfonate in dry DMF (10 mL) (Intermediate 169, 1.2 eq, 2.00 mmol). The reaction was stirred at room temperature overnight. It was quenched with a small amount of water and concentrated to dryness. Residual DMF was removed by co-evaporating with toluene and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The biphasic mixture was filtered, the phases separated and the aqueous phase was back extracted two times with ethyl acetate (2×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with a gradient of 10-20% acetone in hexanes gave 240 mg (27%) of product as a colorless solid.

Workup

  1. temperaturewith cooling in an ice bath
  2. temperatureThe reaction was again cooled in an ice bath
  3. stirringThe reaction was stirred at room temperature overnight
  4. customIt was quenched with a small amount of water
  5. concentrationconcentrated to dryness
  6. customResidual DMF was removed by co-evaporating with toluene
  7. customthe residue was partitioned between ethyl acetate (50 mL) and water (20 mL)
  8. filtrationThe biphasic mixture was filtered
  9. customthe phases separated
  10. extractionthe aqueous phase was back extracted two times with ethyl acetate (2×50 mL)
  11. dry with materialThe combined organic phases were dried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-8f9574d0f5554effb927c501a2752b29
Source dataset
uspto-grants-2011_01
Patent number
US07875715B2

Reaction notes

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