Methanol → Robenacoxib

HRID 1242244Notes

Reaction equation

HRID 1242244 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-86fa4911d04f448289d319ce01431c4d
Source dataset
uspto-grants-2006_10
Patent number
US07115662B2

Reaction notes

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