Acetic Acid → HCID 18700088, compound

HRID 1740616Notes

Reaction equation

HRID 1740616 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CC#N)=[C:17]([O:24][C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:53]([OH:56])(=[O:55])[CH3:54]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:54][C:53]([OH:56])=[O:55])=[C:17]([O:24][C:25]([F:28])([F:26])[F:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 90495Di-tert-butyl dicarbonateHCID 18700100HCID 18700100, compound

Product 1

HCID 18700088HCID 18700088, compound

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrile (1.9 g, 4.3 mmol) from Step 8 above dissolved in a 2:1 mixture of acetic acid and concentrated aqueous HCl (25 mL). Loss of the Boc group occurred within the first 5 minutes to give an intermediate which had an HPLC retention time of 6.3 min (method A). The solution was then refluxed for 2 h, during which time the 6.3 min peak disappeared and a new peak at 5.9 min appeared. The solvents were removed under reduced pressure. The residue was dissolved in degassed DMF (100 mL) and the solvent was removed under reduced pressure to minimize the amount of residual acetic acid and water in the sample. The crude product, 4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, was dissolved in DMF (50 mL) and di-tert-butyldicarbonate (1.0 g, 4.6 mmol) and DIEA (2.3 mL, 13 mmol) were added. The solution was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL). The organic phase was separated, washed with water (2×25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid as a gum (HPLC retention time=10.2 min (method A)).

Workup

  1. customoccurred within the first 5 minutes
  2. customto give an intermediate which
  3. temperatureThe solution was then refluxed for 2 h, during which time the 6.3 min peak
  4. customThe solvents were removed under reduced pressure
  5. dissolutionThe residue was dissolved in degassed DMF (100 mL)
  6. customthe solvent was removed under reduced pressure
  7. dissolutionThe crude product, 4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, was dissolved in DMF (50 mL)
  8. customThe solvent was removed under reduced pressure
  9. customthe residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL)
  10. customThe organic phase was separated
  11. washwashed with water (2×25 mL)
  12. dry with materialdried (MgSO4)
  13. filtrationfiltered
  14. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-bd5df34c8e514f0da612ba4bdfa6f8b0
Source dataset
uspto-grants-1999_10
Patent number
US05968938

Reaction notes

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