Isopropyl iodide → HCID 59201199, compound

HRID 1942298Notes

Reaction equation

HRID 1942298 reaction equation
[OH-].[K+].[OH:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].I[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>CS(C)=O.CO>[CH:32]([O:3][CH2:4][C@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C@H:12]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])([CH3:34])[CH3:33]

Participants

7

Reactant 4

HCID 6362Isopropyl iodide2×HCID 14797Potassium HydroxideHCID 14798Sodium HydroxideHCID 59201214HCID 59201214, compound

Product 1

HCID 59201199HCID 59201199, compoundYield 13.5%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 887MethanolSolvent

Procedure

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.

Workup

  1. customThe reaction was quenched with saturated aqueous NH4Cl
  2. custompartitioned between DCM and H2O
  3. extractionThe aqueous layer was extracted with DCM (×3)
  4. customThe combined extracts were evaporated
  5. additionthe residue was diluted with MeOH
  6. washThe cartridge was eluted with MeOH
  7. washto wash off the DMSO
  8. wash2N NH3 in MeOH to elute the products
  9. customevaporated
  10. temperatureheated to 60° C. for 2 hrs
  11. customwas removed in vacuo
  12. customthe residue was partitioned between DCM and H2O
  13. addition2N HCl (0.5 ml) was added
  14. extractionThe aqueous layer was extracted with DCM (×3)
  15. dry with materialThe combined extracts were dried (Na2SO4)
  16. filtrationfiltered
  17. customevaporated
  18. customThe residue was purified by reverse phase HPLC (ABZ+ column)

Sources & evidence

ORD record
ord-31c04cbff2544921b735c476472cee5c
Source dataset
uspto-grants-2013_03
Patent number
US08389547B2

Reaction notes

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