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

HRID 2089258Notes

Reaction equation

HRID 2089258 reaction equation
[C:1](=[O:4])([O-])O.[Na+].[CH:6]([O:9][C:10](=[O:12])[CH3:11])(C)C.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].CC(C(Cl)=O)C(Cl)=O>>[O:4]=[C:1]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=1)[CH2:11][C:10]([O:9][CH3:6])=[O:12]

Participants

5

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 7915Isopropyl AcetateHCID 516892Sodium BicarbonateHCID 10931669Methylmalonylchloride

Product 1

HCID 58816550Methyl 2-{[3-(trifluoromethyl)phenyl]carbamoyl}acetateYield 91%

Conditions

Temperature
5 °C

Procedure

Sodium hydrogen carbonate (36.3 kg, 1.7 mol eq) was charged followed by iso-propylacetate (102.5 L, 2.5 rel vol). 3-(trifluoromethyl)aniline (41.0 kg, 1 mol eq, limiting reagent) charged followed by a line rinse of iso-propylacetate (20.5 L, 0.5 rel vol). The reaction was cooled to 5° C.-10° C. Methyl malonyl chloride (36.5 kg, 1.05 mol eq) was charged maintaining the temperature below 10° C. followed by a line rinse of iso-propylacetate (10.3 L, 0.25 rel vol). The mixture was stirred until the reaction was complete as judged by HPLC. The temperature was adjusted to 20° C. and further iso-propylacetate (71.8 L, 1.75 rel vol) charged followed by water (205 L, 5 rel vol). The layers were separated & the organic layer further extracted with brine (41 L, 1 rel vol). The solvent was swapped from iso-propylacetate to cyclohexane by reduced pressure distillation. Following seeding, cooling to 5° C. and stirring, the product was isolated by filtration, washed twice with cyclohexane (2×41 L, 2×1 rel vol) and dried to constant weight to yield the title compound (60.6 kg, 232.2 mol, 91%).

Workup

  1. additioncharged
  2. washrinse of iso-propylacetate (20.5 L, 0.5 rel vol)
  3. temperatureThe reaction was cooled to 5° C.-10° C
  4. temperaturemaintaining the temperature below 10° C.
  5. washrinse of iso-propylacetate (10.3 L, 0.25 rel vol)
  6. customwas adjusted to 20° C.
  7. additionfurther iso-propylacetate (71.8 L, 1.75 rel vol) charged
  8. customThe layers were separated
  9. extractionthe organic layer further extracted with brine (41 L, 1 rel vol)
  10. distillationThe solvent was swapped from iso-propylacetate to cyclohexane by reduced pressure distillation
  11. stirringstirring
  12. customthe product was isolated by filtration
  13. washwashed twice with cyclohexane (2×41 L, 2×1 rel vol)
  14. customdried to constant weight

Sources & evidence

ORD record
ord-ce1fa4419eb1414b9df845511886c7e9
Source dataset
uspto-grants-2013_05
Patent number
US08436024B2

Reaction notes

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