Reaktion #2029480

Reaktionsgleichung

KOH

NaOH

2-iodopropane

2-iodopropane

(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl acetic

{(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid

→

title compound

Ausbeute 13.5%

{(2S,4R)-1-[(1R)-1-(Isopropoxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid

Ausbeute 13.5%

Lösungsmittel

DMSO

DMSO

MeOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe reaction was quenched with saturated aqueous NH4Cl
2. 2
   Sonstigepartitioned between DCM and H2O
3. 3
   ExtraktionThe aqueous layer was extracted with DCM (×3)
4. 4
   SonstigeThe combined extracts were evaporated
5. 5
   workup.ADDITIONthe residue was diluted with MeOH
6. 6
   WaschenThe cartridge was eluted with MeOH
7. 7
   Waschento wash off the DMSO
8. 8
   Waschen2N NH3 in MeOH to elute the products
9. 9
   Sonstigeevaporated
10. 10
    Temperaturheated to 60° C. for 2 hrs
11. 11
    Sonstigewas removed in vacuo
12. 12
    Sonstigethe residue was partitioned between DCM and H2O
13. 13
    workup.ADDITION2N HCl (0.5 ml) was added
14. 14
    ExtraktionThe aqueous layer was extracted with DCM (×3)
15. 15
    TrocknenThe combined extracts were dried (Na2SO4)
16. 16
    Filtrationfiltered
17. 17
    Sonstigeevaporated
18. 18
    SonstigeThe residue was purified by reverse phase HPLC (ABZ+ column)

Vorschrift

Powdered KOH (375 mg, 6.68 mmol) was taken up in dry DMSO (1 ml) at RT under N2. The mixture was stirred for 10 minutes before the addition of {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl acetic}acid (Step 1, 67 mg, 0.167 mmol) in dry DMSO (0.5+0.5+0.5 ml), followed by 2-iodopropane (0.334 ml, 3.34 mmol). After 24 hr MS further 2-iodopropane (0.334 ml, 3.34 mmol) was added and the reaction was maintained at RT for 3 days. The reaction was quenched with saturated aqueous NH4Cl and then partitioned between DCM and H2O. The aqueous layer was extracted with DCM (×3). The combined extracts were evaporated and the residue was diluted with MeOH and loaded on to a SCX cartridge (2 g). The cartridge was eluted with MeOH to wash off the DMSO, then 2N NH3 in MeOH to elute the products. The NH3/MeOH fractions were combined and evaporated. The residue was taken up in MeOH (2 ml) and 4N NaOH (aq, 0.2 ml, 0.8 mmol) was added. The mixture was stirred and heated to 60° C. for 2 hrs. After cooling to RT the MeOH was removed in vacuo and the residue was partitioned between DCM and H2O. 2N HCl (0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by reverse phase HPLC (ABZ+ column) to give the title compound (10 mg) as a colourless solid.

Quelle