Water → Methyl 2-{[3-(trifluoromethyl)phenyl]carbamoyl}acetate

HRID 1517463Notes

Reaction equation

HRID 1517463 reaction equation
[C:1](=O)([O-])[OH:2].[Na+].[F:6][C:7]([F:16])([F:15])[C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].C[CH:18]([C:22](Cl)=O)[C:19](Cl)=[O:20].[OH2:25]>CC(C)=O>[O:25]=[C:22]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([C:7]([F:15])([F:16])[F:6])[CH:9]=1)[CH2:18][C:19]([O:2][CH3:1])=[O:20]

Participants

6

Reactant 4

HCID 962WaterHCID 73753-(Trifluoromethyl)anilineHCID 516892Sodium BicarbonateHCID 10931669Methylmalonylchloride

Product 1

HCID 58816550Methyl 2-{[3-(trifluoromethyl)phenyl]carbamoyl}acetateYield 84%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent3×

Conditions

Temperature
0 °C

Procedure

Sodium hydrogen carbonate (26.0 kg, 1.7 mol eq) was charged followed by acetone (58.6 L, 2 rel vol). 3-(Trifluoromethyl)aniline (29.3 kg, 1 mol eq, limiting reagent) was charged followed by addition of acetone (14.7 L, 0.5 rel vol) and the mixture cooled to 0° C. Methyl malonyl chloride (25.8 kg, 1.05 mol eq) was diluted with acetone (29.3 L, 1 rel vol) and charged maintaining the temperature below 20° C. An acetone line rinse (14.7 L, 0.5 rel vol) was charged and the reaction mixture was stirred until HPLC confirmed the reaction to be complete. Water (293 L, 10 rel vol) was then charged and acetone was removed by distillation. The reaction was then cooled to 20° C. A further portion of water was added (171.2 L, 4 rel vol) and the reaction was stirred to precipitate out the product. The solid was isolated by filtration, washed twice with water (2×58.6 L, 2×2 rel vol), once with iso-hexane (146.5 L, 5 rel vol) and dried to constant weight to yield the title compound (39.5 kg, 151.7 mol, 84%); 1H NMR (CDCl3): δ 3.51 (s, 2H); 3.82 (s, 3H); 7.38 (d, 1H, J=7.9 Hz); 7.45 (t, 1H, J=7.9 Hz); 7.76 (d, 1H, J=7.7 Hz); 7.85 (s, 1H); 9.42 (s, 1H) ppm; LCMS: m/z 262.2 (MH+).

Workup

  1. additionwas charged
  2. additioncharged
  3. temperaturemaintaining the temperature below 20° C
  4. washAn acetone line rinse (14.7 L, 0.5 rel vol)
  5. additionwas charged
  6. customthe reaction
  7. customacetone was removed by distillation
  8. temperatureThe reaction was then cooled to 20° C
  9. additionA further portion of water was added (171.2 L, 4 rel vol)
  10. stirringthe reaction was stirred
  11. customto precipitate out the product
  12. customThe solid was isolated by filtration
  13. washwashed twice with water (2×58.6 L, 2×2 rel vol), once with iso-hexane (146.5 L, 5 rel vol)
  14. customdried to constant weight

Sources & evidence

ORD record
ord-58779a01773641d9b61f78b2a956c56d
Source dataset
uspto-grants-2012_07
Patent number
US08232296B2

Reaction notes

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