Diphenyl Ether → Tolmetin

HRID 1389725Notes

Reaction equation

HRID 1389725 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[Na].[C:11]([C:13]1[N:17]([CH3:18])[C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)#N.C1([O:29]C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:18][N:17]1[C:13]([C:11]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:29])=[CH:14][CH:15]=[C:16]1[CH2:19][C:20]([OH:22])=[O:21]

Participants

7

Reactant 5

HCID 7583Diphenyl EtherHCID 78054-BromotolueneHCID 5360545SodiumHCID 5462224MagnesiumHCID 155715345-cyano-1-methyl-1H-pyrrole-2-acetic acid2×

Product 1

HCID 5509TolmetinYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of the Grignard reagent prepared from 0.46 g. (20 mmol) of magnesium and 3.4 g. (20 mmol) of 4-bromotoluene in 15 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen 1.12 g. (6.0 mmol) of the sodium salt of 5-cyano-1-methylpyrrole-2-acetic acid. To the resulting suspension was added 20 g. of diphenyl ether, and the reaction mixture was heated to remove tetrahydrofuran by distillation until the temperature reached 110° C. The reaction mixture was then successively heated under reflux at 110° C. for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was worked up in the manner described in Example 1 to give 100 mg. (9%) of purple solid that contained mainly 5-cyano-1-methylpyrrole-2-acetic acid by nmr analysis. The aqueous phase was heated in a steam bath for 7 hours and the product was isolated after extraction with methylene chloride to give 1.15 g. (yield: 75%, 83% based on unrecovered cyanoacid) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as a brown solid.

Workup

  1. additionTo the resulting suspension was added 20 g
  2. customto remove tetrahydrofuran
  3. distillationby distillation until the temperature
  4. customreached 110° C
  5. temperatureThe reaction mixture was then successively heated
  6. temperaturecooled
  7. custompartitioned between ether and dilute aqueous hydrochloric acid
  8. customto give 100 mg
  9. temperatureThe aqueous phase was heated in a steam bath for 7 hours
  10. customthe product was isolated
  11. extractionafter extraction with methylene chloride
  12. customto give 1.15 g

Sources & evidence

ORD record
ord-15b2440f5319462f8977383002d5ab5a
Source dataset
uspto-grants-1981_01
Patent number
US04246176

Reaction notes

Loading…