Citric Acid → Tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzamido)-4-phenylbenzoyloxy)piperidine-1-carboxylate

HRID 454623Notes

Reaction equation

HRID 454623 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](=[O:18])([O-:17])[O-].[Cs+].[Cs+].[N:21]1[C:34]2[C:25](=CC=C3C=2N=CC=C3)[CH:24]=[CH:23][CH:22]=1.[CH2:35]([O:42][C:43]1[CH:70]=[CH:69][C:68](I)=[CH:67][C:44]=1[C:45]([NH:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52]C(C)(C)C)=[O:51])=[O:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)[CH2:73][C:74]([CH2:79]C(O)=O)([C:76](O)=O)O>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:35]([O:42][C:43]1[CH:70]=[CH:69][C:68]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:67][C:44]=1[C:45]([NH:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52][CH:24]1[CH2:25][CH2:34][N:21]([C:15]([O:17][C:74]([CH3:79])([CH3:76])[CH3:73])=[O:18])[CH2:22][CH2:23]1)=[O:51])=[O:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1

Participants

9

Reactant 5

HCID 311Citric AcidHCID 13181,10-Phenanthroline3×HCID 10796Cesium carbonate2×HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylate2×HCID 66990274Tert-butyl 2-(2-(benzyloxy)-5-iodobenzamido)-4-phenylbenzoate

Product 1

HCID 66990014Tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzamido)-4-phenylbenzoyloxy)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst3×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (0.047 g), cesium carbonate (0.075 g), 1,10-phenanthroline (4.2 mg), and copper(I) iodide (2.2 mg) were added to a toluene (1 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-iodobenzamido)-4-phenylbenzoate (0.070 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (0.047 g), cesium carbonate (0.075 g), 1,10-phenanthroline (4.2 mg), and copper(I) iodide (2.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then 1,10-phenanthroline (4.2 mg) and copper(I) iodide (2.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then 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: 95-60% hexane/ethyl acetate] to obtain 0.074 g of tert-butyl 4-(2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzamido)-4-phenylbenzoyloxy)piperidine-1-carboxylate.

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 2 hours
  5. temperatureThe reaction mixture was cooled to room temperature
  6. temperatureby heating
  7. temperatureto reflux under a nitrogen atmosphere for 5 hours and 30 minutes
  8. temperatureThe reaction mixture was cooled to room temperature
  9. customThe insoluble substance was removed by filtration
  10. customThe organic layer was separated
  11. washwashed with a saturated aqueous solution of sodium chloride
  12. dry with materialdried over anhydrous magnesium sulfate
  13. customthe solvent was evaporated under reduced pressure
  14. customThe obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-60% hexane/ethyl acetate]

Sources & evidence

ORD record
ord-eccded8063ff4e68a7f69c0abf9eb0b4
Source dataset
uspto-grants-2013_07
Patent number
US08492582B2

Reaction notes

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