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

HRID 1692182Notes

Reaction equation

HRID 1692182 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 12.6 g (0.21 mol) of acetic acid. 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. Then 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (21 g, 0.10 mol) (i.e. the product of Example 1) 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. After about 20 minutes, when no more than 0.5% 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione remained, water (50 mL) was added. 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, >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. temperaturewas maintained at 40-45° C.
  5. distillationethyl acetate was distilled out at an internal temperature of about 46-60° C. and pressure of about 30 to 50 kPa
  6. customremoved by distillation, water
  7. additionwas added
  8. temperatureto maintain the original liquid volume in the reactor
  9. distillationto distill
  10. temperaturethe aqueous slurry was cooled to 10° C
  11. filtrationThe solid was collected by filtration
  12. customdried at 60° C.

Sources & evidence

ORD record
ord-255464e7c51f46f688e923fa60e16a09
Source dataset
uspto-grants-2012_04
Patent number
US08153844B2

Reaction notes

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