Acetic Anhydride → Mebrofenin

HRID 1649576Notes

Reaction equation

HRID 1649576 reaction equation
[N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29]

Participants

5

Reactant 3

HCID 7918Acetic AnhydrideHCID 8758Nitrilotriacetic AcidHCID 6883003-Bromo-2,4,6-trimethylaniline

Product 1

HCID 54158MebrofeninYield 47%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent2×

Conditions

Temperature
50 °C

Procedure

A suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves) is prepared with the exclusion of moisture (CaSO4 drying tube) and heated to 50° C. Acetic anhydride (5.11 g) is added dropwise. The reaction mixture clears and is heated to 100° C. After maintaining the temperature for 40 minutes, the reaction mixture is cooled to 55° C. and a solution of 10.7 g 3-bromo-2,4,6-trimethylaniline in 25 ml of dry pyridine is added slowly. The reaction is heated to 100° C. and after 1.5 hours at this temperature, the solution is cooled in an ice-bath. The reaction mixture is rotary evaporated to a semisolid which is dissolved in 125 ml of 10% sodium hydroxide w/v. The basic layer is then extracted with two 100 ml portions of methylene chloride. Distilled water (100 ml) is added to the basic layer which is then brought to pH 3 with concentrated hydrochloric acid to give a precipitate. After refrigeration for about 16 hours, the crude product is filtered, washed with cold distilled water and dried under vacuum at 40° C. The crude product is dissolved in 100 ml of 60% aqueous ethanol, treated with 3.0 g of Darco and filtered hot through a Hyflo-bed to give a solution. Crystals precipitate and are filtered, washed with three 25 ml portions of 50% aqueous ethanol and dried under vacuum at 40° C. The reaction yields 9.1 g of the title compound, melting point 198°-200° C., dec.

Workup

  1. temperatureis heated to 100° C
  2. temperatureAfter maintaining the temperature for 40 minutes
  3. temperaturethe reaction mixture is cooled to 55° C.
  4. temperatureThe reaction is heated to 100° C. and after 1.5 hours at this temperature
  5. temperaturethe solution is cooled in an ice-bath
  6. customThe reaction mixture is rotary evaporated to a semisolid which
  7. dissolutionis dissolved in 125 ml of 10% sodium hydroxide
  8. extractionThe basic layer is then extracted with two 100 ml portions of methylene chloride
  9. additionDistilled water (100 ml) is added to the basic layer which
  10. customto give a precipitate
  11. filtrationthe crude product is filtered
  12. washwashed
  13. distillationwith cold distilled water
  14. customdried under vacuum at 40° C
  15. dissolutionThe crude product is dissolved in 100 ml of 60% aqueous ethanol
  16. additiontreated with 3.0 g of Darco
  17. filtrationfiltered hot through a Hyflo-bed
  18. customto give a solution
  19. filtrationCrystals precipitate and are filtered
  20. washwashed with three 25 ml portions of 50% aqueous ethanol
  21. customdried under vacuum at 40° C

Sources & evidence

ORD record
ord-b0740da0a2894588ad6c9b631042d7c0
Source dataset
uspto-grants-1983_11
Patent number
US04418208

Reaction notes

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