Acetic Acid → 2-Amino-5-Chloro-N,3-Dimethylbenzamide

HRID 1663510Notes

Reaction equation

HRID 1663510 reaction equation
C(OCC)(=O)C.C(O)(=O)C.[CH3:11][NH2:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH3:26])[C:17]2[NH:22]C(=O)[O:20][C:19](=O)[C:18]=2[CH:25]=1>O>[NH2:22][C:17]1[C:16]([CH3:26])=[CH:15][C:14]([Cl:13])=[CH:25][C:18]=1[C:19]([NH:12][CH3:11])=[O:20]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 6329MethylamineHCID 8857Ethyl AcetateHCID 115502595-Chloro-3-methyl isatoic anhydride3×

Product 1

HCID 250682512-Amino-5-Chloro-N,3-DimethylbenzamideYield 95.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
37.5 °C

Procedure

A 300-mL flask equipped with a thermometer and nitrogen bubbler was charged with ethyl acetate (100 mL) and acetic acid (12.6 g, 0.21 mol). Anhydrous methylamine (6.3 g, 0.20 mol) was added below the surface of the liquid mixture, which was cooled to maintain the temperature below 35° C., and then 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (21 g, 0.10 mol) (see Scheme 4 for a method of preparation) was added in portions while maintaining the reaction mixture at 35-40° C. After completion of the addition of the 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione the temperature was maintained at 40-45° C., and the progress of the reaction was monitored by HPLC analysis. When analysis of the reaction mixture indicated no more than 0.5% of the 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione remained (about 20 minutes), water (50 mL) was added to the reaction mixture. A distillation head was attached, moderate vacuum was applied, and ethyl acetate was distilled out at an internal temperature of about 46-60° C. and pressure of about 30 to 50 kPa. To replace the ethyl acetate removed by distillation, water was added to maintain the original liquid volume in the reactor. When a significant amount of water began to distill, the aqueous slurry was cooled to 10° C. The solid was collected by filtration and dried at 60° C. and 13.3 kPa to afford the title compound as a white crystalline solid (19 g, ca. 95% yield, above 98% purity by peak area in HPLC analysis).

Workup

  1. customA 300-mL flask equipped with a thermometer and nitrogen bubbler
  2. temperaturewas cooled
  3. temperatureto maintain the temperature below 35° C.
  4. customfor a method of preparation)
  5. additionwas added in portions
  6. temperaturewas maintained at 40-45° C.
  7. additionwas added to the reaction mixture
  8. distillationethyl acetate was distilled out at an internal temperature of about 46-60° C. and pressure of about 30 to 50 kPa
  9. customremoved by distillation, water
  10. additionwas added
  11. temperatureto maintain the original liquid volume in the reactor
  12. distillationto distill
  13. temperaturethe aqueous slurry was cooled to 10° C
  14. filtrationThe solid was collected by filtration
  15. customdried at 60° C.

Sources & evidence

ORD record
ord-a5a8cfd06609488e8152488e063fae47
Source dataset
uspto-grants-2011_10
Patent number
US08034968B2

Reaction notes

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