Methanol → Robenacoxib

HRID 1280847Notes

Reaction equation

HRID 1280847 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:22].C[OH:24].[OH-].[Na+]>O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=2[F:10])=[C:14]([CH2:13][C:12]([OH:24])=[O:22])[CH:15]=1)[CH3:21]

Participants

5

Reactant 3

HCID 887MethanolHCID 14798Sodium HydroxideHCID 219386525-Ethyl-1,3-dihydro-1-(2,3,5,6-tetrafluorophenyl)-2H-indol-2-one

Product 1

HCID 6433107Robenacoxib

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol, is slurried in water containing a little methanol (10% v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture is stirred at 80-85° for 2-4 hours, then cooled to ambient temperature. The reaction solution is partially concentrated under reduced pressure (25-30 mm). After removal of 50 ml of the solvent, the mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml). The cooled mixture is acidified to pH 6.5-7.0 with aqueous HCl (12.1 N; 19.5 ml), keeping the temperature at 0-5°. The aqueous layer is discarded and the organic layer is washed with water (250 ml). The organic layer is concentrated under reduced pressure (20-100 mm) while exchanging the solvent to toluene. After the more volatile components have been removed, the batch volume is adjusted to 400-450 ml. This mixture is warmed to 70°, clarified, concentrated to one-half volume, and cooled to 0°. After stirring at this temperature for 2 hours, the product is collected and is washed with toluene/heptane (10:90; 100 ml). The resulting solid is dried under reduced pressure at 50-60° for 4-8 hours to give 5-ethyl-2-(2′, 3′, 5′, 6′-tetrafluoroanilino)phenylacetic acid of Example 3.

Workup

  1. additionis added
  2. concentrationThe reaction solution is partially concentrated under reduced pressure (25-30 mm)
  3. customAfter removal of 50 ml of the solvent
  4. additionthe mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml)
  5. customat 0-5°
  6. washthe organic layer is washed with water (250 ml)
  7. concentrationThe organic layer is concentrated under reduced pressure (20-100 mm)
  8. customAfter the more volatile components have been removed
  9. temperatureThis mixture is warmed to 70°
  10. concentrationconcentrated to one-half volume
  11. temperaturecooled to 0°
  12. stirringAfter stirring at this temperature for 2 hours
  13. customthe product is collected
  14. washis washed with toluene/heptane (10:90; 100 ml)
  15. customThe resulting solid is dried under reduced pressure at 50-60° for 4-8 hours

Sources & evidence

ORD record
ord-03bf28bee7214d6984e5ce22da0d7fbe
Source dataset
uspto-grants-2002_09
Patent number
US06451858B2

Reaction notes

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