Water → 1-[2-[3-(3,4-Difluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide

HRID 400053Notes

Reaction equation

HRID 400053 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]2([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:42]=1.O>O1CCCC1.ClCCl.CO>[F:20][C:15]1[CH:14]=[C:13]([C:10]2([CH2:21][CH2:22][N:50]3[CH2:49][CH2:48][C:47]([C:43]4[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=4)([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[F:19]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 543724704-(Pyrid-3-yl)-piperidine-4-carboxylic acid amideHCID 867532452-[1-(3,4,5-Trimethoxy-benzoyl)-3-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate

Product 1

HCID 676479721-[2-[3-(3,4-Difluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21226129Dichloromethane methanolSolvent5×

Procedure

Combine 2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (prepared from (-)-2-[3-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (R,R)-di-p-anisoyltartaric acid salt)(0.6 g, 1.2 mmol), potassium carbonate (0.46 g, 3.4 mmol), and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide in tetrahydrofuran (6 mL)/ water (2 mL). Heat to reflux. After 64 hours, evaporate the reaction mixture in vacuo to remove most of the tetrahydrofuran and combine with dichloromethane. Extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1% methanol/dichloromethane, 3% methanol/dichloromethane, 5% methanol/dichloromethane, dichloromethane/methanol/concentrated ammonia (464/35/2.5) and then, dichloromethane/methanol/concentrated ammonia (450/50/2.5) to give the title compound: Rf =0.17 (silica gel, dichloromethane/methanol/concentrated ammonia 9/1/0.05).

Workup

  1. temperatureHeat to reflux
  2. customevaporate the reaction mixture in vacuo
  3. customto remove most of the tetrahydrofuran
  4. extractionExtract with a saturated aqueous solution of sodium bicarbonate
  5. dry with materialDry the organic layer over MgSO4
  6. filtrationfilter
  7. concentrationconcentrate in vacuo
  8. customto give a residue

Sources & evidence

ORD record
ord-7aa42c0d846c47fbbf0e2693c18be36f
Source dataset
uspto-grants-1998_10
Patent number
US05824690

Reaction notes

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