Sodium hydride → 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

HRID 1985198Notes

Reaction equation

HRID 1985198 reaction equation
[H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CN(C=O)C>[CH3:32][C:7]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][C:35]([F:34])([F:45])[F:46])=[CH:38][CH:39]=3)[C:20](=[O:23])[N:19]2[CH3:24])=[CH:13][CH:14]=1)[C:6]([OH:5])=[O:33]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1427851-(Bromomethyl)-4-(trifluoromethoxy)benzeneHCID 688674462-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester

Product 1

HCID 688671722-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acidYield 32%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (8.8 mg, 0.22 mmol, 60% w/w in mineral oil) is added to a cooled (0° C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (78.5 mg, 0.18 mmol) in DMF (1 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over one hour. After the solution is cooled again to 0° C., 4-(trifluoromethoxy)benzyl bromide (59 ul, 0.37 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in methanol (5 ml), treated with 5N NaOH (0.5 ml), and stirred for 14 hours at ambient temperature. After concentration to remove methanol, the residue is partitioned between diethyl ether and water. The aqueous layer is adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to yield an oil (33 mg, 31%).

Workup

  1. customthe reaction mixture is removed from the cooling bath
  2. temperatureAfter the solution is cooled again to 0° C.
  3. customthe cooling bath removed
  4. stirringthe mixture stirred for one hour
  5. customThe reaction mixture is quenched with 1N HCl
  6. extractionextracted with ethyl acetate (2×)
  7. washThe organic extracts were washed with water, brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated to an oil
  10. dissolutionThe crude product is dissolved in methanol (5 ml)
  11. additiontreated with 5N NaOH (0.5 ml)
  12. stirringstirred for 14 hours at ambient temperature
  13. concentrationAfter concentration
  14. customto remove methanol
  15. customthe residue is partitioned between diethyl ether and water
  16. extractionextracted with ethyl acetate (2×15 ml)
  17. washThe combined ethyl acetate extracts were washed with water, brine
  18. dry with materialdried (Na2SO4)
  19. concentrationconcentrated to an oil which
  20. customis purified by MS/LC

Sources & evidence

ORD record
ord-93db68559d4b40999f7ce3429ea22a82
Source dataset
uspto-grants-2009_06
Patent number
US07544812B2

Reaction notes

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