Diphenyl Ether → Tolmetin

HRID 1389724Notes

Reaction equation

HRID 1389724 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]([C:12]1[N:16]([CH3:17])[C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)#N.C1([O:28]C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:17][N:16]1[C:12]([C:10]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:28])=[CH:13][CH:14]=[C:15]1[CH2:18][C:19]([OH:21])=[O:20]

Participants

6

Reactant 4

HCID 7583Diphenyl EtherHCID 78054-BromotolueneHCID 5462224MagnesiumHCID 155715345-cyano-1-methyl-1H-pyrrole-2-acetic acid

Product 1

HCID 5509TolmetinYield 86%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
110 °C

Procedure

To a solution of the Grignard reagent prepared from 0.71 g. (31 mmol) of magnesium and 5.3 g. (31 mmol) of 4-bromotoluene in 20 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen a solution of 0.98 g. (6.0 mmol) of 5-cyano-1-methylpyrrole-2-acetic acid in 5 ml. of tetrahydrofuran. After the resulting yellow suspension was heated to the boiling point, 20 g. of diphenyl ether was added, and tetrahydrofuran was distilled from the reaction mixture until the temperature reached 110° C. The reaction mixture was then heated under reflux (110° C.) for 1.5 hours. During this time, the color of the suspension changed from yellow to dark orange. The reaction mixture was cooled and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was extracted with five percent aqueous sodium hydroxide solution, which was then acidified and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 30 mg. of purple liquid which contained only a trace of starting cyanoacid by nmr analysis. The aqueous phase was heated in a steam bath for four hours, and the resulting suspension was cooled and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 1.33 g. (86% yield) of 1-methyl-5-p-toluoyl-pyrrole-2-acetic acid as a brown solid.

Workup

  1. temperatureAfter the resulting yellow suspension was heated to the boiling point, 20 g
  2. distillationtetrahydrofuran was distilled from the reaction mixture until the temperature
  3. customreached 110° C
  4. temperatureThe reaction mixture was then heated
  5. temperatureThe reaction mixture was cooled
  6. custompartitioned between ether and dilute aqueous hydrochloric acid
  7. extractionThe ether phase was extracted with five percent aqueous sodium hydroxide solution, which
  8. extractionextracted with methylene chloride
  9. dry with materialThe methylene chloride solution was dried over magnesium sulfate
  10. concentrationconcentrated
  11. customto give 30 mg
  12. temperatureThe aqueous phase was heated in a steam bath for four hours
  13. temperaturethe resulting suspension was cooled
  14. extractionextracted with methylene chloride
  15. dry with materialThe methylene chloride solution was dried over magnesium sulfate
  16. concentrationconcentrated
  17. customto give 1.33 g

Sources & evidence

ORD record
ord-1d4fda969b6e4bb89ef684de277f19ff
Source dataset
uspto-grants-1981_01
Patent number
US04246176

Reaction notes

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