4-Bromotoluene → Tolmetin

HRID 1389726Notes

Reaction equation

HRID 1389726 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]([O-:21])=[O:20])=[CH:14][CH:13]=1)#N.[Ca].C(C1N(C)C(CC(O)=[O:33])=CC=1)#N>O.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:33])=[CH:13][CH:14]=[C:15]1[CH2:18][C:19]([OH:21])=[O:20]

Participants

8

Reactant 5

HCID 78054-BromotolueneHCID 5460341CalciumHCID 5462224MagnesiumHCID 155715345-cyano-1-methyl-1H-pyrrole-2-acetic acidHCID 202952105-Cyano-1-methylpyrrole-2-acetate

Product 1

HCID 5509TolmetinYield 63%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of the Grignard reagent prepared from 0.82 g. (36 mmol) of magnesium and 6.2 g. (36 mmol) of 4-bromotoluene in 15 ml. of anhydrous tetrahydrofuran was added 1.2 g. of solid material which contained about 6.0 mmol of 5-cyano-1-methylpyrrole-2-acetate as the calcium salt and some water which persisted after drying in a vacuum oven. Diphenyl ether (20 g.) was added, and the reaction mixture was heated to remove tetrahydrofuran by distillation until the temperature reached 110° C. The reaction mixture was then heated under reflux for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. Following a work-up procedure similar to that described for Example 1, there was obtained 130 mg. (13%) of 5-cyano-1-methylpyrrole-2-acetic acid and 970 mg. (yield: 63%, 73% based on unrecovered cyanoacid) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as brown solids.

Workup

  1. customafter drying in a vacuum oven
  2. additionDiphenyl ether (20 g.) was added
  3. temperaturethe reaction mixture was heated
  4. customto remove tetrahydrofuran
  5. distillationby distillation until the temperature
  6. customreached 110° C
  7. temperatureThe reaction mixture was then heated
  8. temperatureunder reflux for two hours
  9. temperaturecooled
  10. custompartitioned between ether and dilute aqueous hydrochloric acid
  11. customthere was obtained 130 mg

Sources & evidence

ORD record
ord-c2d22e67c8cd46d9a10ea662fba86948
Source dataset
uspto-grants-1981_01
Patent number
US04246176

Reaction notes

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