Reaktion #1827798

Reaktionsgleichung

4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetonitrile

acetic acid

di-tert-butyldicarbonate

DIEA

→

4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid

Lösungsmittel

HCl

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigeoccurred within the first 5 minutes
2. 2
   Sonstigeto give an intermediate which
3. 3
   TemperaturThe solution was then refluxed for 2 h, during which time the 6.3 min peak
4. 4
   SonstigeThe solvents were removed under reduced pressure
5. 5
   workup.DISSOLUTIONThe residue was dissolved in degassed DMF (100 mL)
6. 6
   Sonstigethe solvent was removed under reduced pressure
7. 7
   workup.DISSOLUTIONThe crude product, 4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid, was dissolved in DMF (50 mL)
8. 8
   SonstigeThe solvent was removed under reduced pressure
9. 9
   Sonstigethe residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (50 mL)
10. 10
    SonstigeThe organic phase was separated
11. 11
    Waschenwashed with water (2×25 mL)
12. 12
    Trocknendried (MgSO4)
13. 13
    Filtrationfiltered
14. 14
    Sonstigethe solvent was removed under reduced pressure

Vorschrift

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)).

Quelle