Citric Acid → Tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate

HRID 454595Notes

Reaction equation

HRID 454595 reaction equation
[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:13]([O:20][C:21]1[CH:48]=[CH:47][C:46](Br)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:48]=[CH:47][C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1

Participants

10

Reactant 4

HCID 311Citric AcidHCID 8082Piperidine2×HCID 10796Cesium carbonate2×HCID 66990333Tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate

Product 1

HCID 66990319Tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalyst2×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalyst2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Piperidine (0.040 mL), cesium carbonate (0.18 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) suspension of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then piperidine (0.040 mL), cesium carbonate (0.18 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-70% hexane/ethyl acetate] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-phenylbenzoate as an orange oily substance.

Workup

  1. temperatureby heating
  2. temperatureto reflux under a nitrogen atmosphere for 4 hours
  3. temperatureby heating
  4. temperatureto reflux under a nitrogen atmosphere for 5 hours and 30 minutes
  5. temperatureThe reaction mixture was cooled to room temperature
  6. customThe insoluble substance was removed by filtration
  7. customThe organic layer was separated
  8. washwashed with a saturated aqueous solution of sodium chloride
  9. dry with materialdried over anhydrous magnesium sulfate
  10. customthe solvent was evaporated under reduced pressure
  11. customThe obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-70% hexane/ethyl acetate]

Sources & evidence

ORD record
ord-fd69c59800144776878ab2f30d8db523
Source dataset
uspto-grants-2013_07
Patent number
US08492582B2

Reaction notes

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