Sulfuric Acid → 2-Methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl)-propyl}-phenoxy)-pentanoic acid ethyl ester

HRID 1985251Notes

Reaction equation

HRID 1985251 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:4][CH:3]=1.Br[C:30]([CH3:37])([CH2:34][CH2:35][CH3:36])[C:31]([OH:33])=[O:32].[CH3:38][C:39](C)([O-])C.[K+].OS(O)(=O)=O>CC(O)(C)C.CCO>[CH2:38]([O:33][C:31](=[O:32])[C:30]([CH3:37])([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH3:36])[CH3:39]

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 219158932-Bromo-2-methylpentanoic acidHCID 23665647Potassium tert-butoxideHCID 577192494-[3-(4-Hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one

Product 1

HCID 577191102-Methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl)-propyl}-phenoxy)-pentanoic acid ethyl esterYield 71%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6386tert-ButanolSolvent2×

Conditions

Temperature
45 °C

Procedure

A mixture of 4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one (0.51 g, 1.30 mmol) and 2-bromo-2-methyl-pentanoic acid (2.54 g, 13.0 mmol) in 2-methyl-2-propanol (10 mL) was heated to 45° C. under N2 and then a solution of 1 M potassium tert-butoxide in 2-methyl-2-propanol (27.3 mL, 27.3 mmol) was added dropwise and the reaction was stirred at 45° C. for 40 minutes. The reaction mixture was cooled and quenched with 1 N HCl (50 mL). The mixture was then diluted with water and extracted with Et2O. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was combined with EtOH (50 mL) and conc. H2SO4 (6 mL). The mixture was heated to reflux for 3 h. The reaction mixture was cooled and the solvent removed in vacuo. The residue was diluted with water and extracted with EtOAc and the organic layer was dried (Na2SO4). The solvent was removed in vacuo to give crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 0.491 g (71%) 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid ethyl ester. This material could be purified by chiral preparative HPLC (conditions,) 1H NMR. MS (ES+) m/z calcd for C29H38N2O4F3 [M+1] 535. Found 535 (100%).

Workup

  1. temperatureThe reaction mixture was cooled
  2. customquenched with 1 N HCl (50 mL)
  3. additionThe mixture was then diluted with water
  4. extractionextracted with Et2O
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. customthe solvent removed in vacuo
  7. customto afford crude product that
  8. temperatureThe mixture was heated
  9. temperatureto reflux for 3 h
  10. temperatureThe reaction mixture was cooled
  11. customthe solvent removed in vacuo
  12. additionThe residue was diluted with water
  13. extractionextracted with EtOAc
  14. dry with materialthe organic layer was dried (Na2SO4)
  15. customThe solvent was removed in vacuo
  16. customto give crude product that
  17. customwas purified by flash chromatography

Sources & evidence

ORD record
ord-814691a51eaa4fffb2d742cabd0135f8
Source dataset
uspto-grants-2009_06
Patent number
US07544812B2

Reaction notes

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