Tetrahydrofuran → 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid

HRID 1691697Notes

Reaction equation

HRID 1691697 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].C1COCC1.Cl[C:46]([O:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55]C)=[O:54])=[CH:51][CH:50]=1)=[O:47]>O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:46]([O:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=2)=[O:47])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 516892Sodium BicarbonateHCID 854163Methyl 4-[(chlorocarbonyl)oxy]benzoateHCID 59178528HCID 59178528, compound

Product 1

HCID 669061994-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acidYield 87.7%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a mixture of 192 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 157 mg of sodium hydrogen carbonate were added 3 mL of THF and 1.5 mL of water, followed by addition of 133 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). It was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 228 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627

Workup

  1. extractionextracted with ethyl acetate
  2. washThe organic layer was washed with water and saturated brine in this order
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationAfter filtration
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. additionto 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution
  7. stirringby stirring at room temperature overnight
  8. additionThe reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid
  9. concentrationconcentrated under reduced pressure
  10. extractionextracted with ethyl acetate
  11. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  12. filtrationfiltered
  13. concentrationthe filtrate was concentrated under reduced pressure
  14. customThe obtained residue was purified by silica gel column chromatography (chloroform-methanol)

Sources & evidence

ORD record
ord-f950c037ebee43818480ba36add641e5
Source dataset
uspto-grants-2012_04
Patent number
US08153658B2

Reaction notes

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