Dimethyl malonate → 3,5-Bis(trifluoromethyl)phenylacetic acid

HRID 1937764Notes

Reaction equation

HRID 1937764 reaction equation
C[O-].[Na+].[C:4](OC)(=O)[CH2:5][C:6]([O:8]C)=[O:7].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=C(Br)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.BrC1C=CC=CC=1.[OH-].[Na+]>[Cu]Br.[Cu]I.O.COCCOC>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:4]([CH2:5][C:6]([OH:8])=[O:7])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1

Participants

10

Reactant 5

HCID 7943Dimethyl malonateHCID 7961BromobenzeneHCID 14798Sodium HydroxideHCID 676021-Bromo-3,5-bis(trifluoromethyl)benzeneHCID 10942334Sodium Methoxide

Product 1

HCID 1235873,5-Bis(trifluoromethyl)phenylacetic acidYield 89%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 24593copper(I) bromideCatalyst2×HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
69 °C

Procedure

550 ml of ethylene glycol dimethyl ether were initially charged and, under nitrogen, 91 g of sodium methoxide (solid) were introduced, giving, without any change in temperature, a white suspension which was readily stirrable. The mixture was heated to 69° C. and 237.6 g of dimethyl malonate were added dropwise over a period of 30 minutes, during which the mixture began to boil under reflux (internal temperature 74° C.) and a stirrable white slurry was formed. After cooling to 54° C., 35.2 g of copper(I) bromide (fine powder) and 35.2 g of copper(I) iodide (fine powder) were added, and the mixture was then again heated at the boil under reflux. Over a period of 110 minutes, 344 g of 3,5-bis-(trifluoromethyl)-bromobenzene were added dropwise, and a gentle stream of waste gas was observed (partial de-methoxycarbonylation). After 15 hours and 40 minutes (conversion monitored by GC) at reflux (85° C.), a further 10 g of copper(I) bromide and a further 10 g of copper(I) iodide were added. After a further 5 hours under reflux at 86° C. (conversion monitored by GC; at least 90% conversion of the bromobenzene employed), 400 g of 45% by weight strength aqueous sodium hydroxide solution were added dropwise at 86° C. (reflux) over a period of 15 minutes and the mixture was kept at reflux at this temperature for a further 4 hours, during which a gentle evolution of waste gas took place. GC analysis then showed that no more ester was present. With stirring, 1000 ml of water were added and the precipitate was allowed to settle. Undissolved particles were then substantially decanted off over a Nutsche and the remaining content of the flask was suspended in 100 ml of 2 N aqueous sodium hydroxide solution and filtered off with suction over the Nutsche. The resulting two-phase filtrate was concentrated at 20 mbar (1350 ml of distillate) and diluted again with 1000 ml of water. Organic impurities were extracted using 30 ml of toluene (1.4 g of residue on concentration using a rotary evaporator) and the aqueous phase was poured into 920 g of 24% by weight strength aqueous sulphuric acid (18-24° C.), which resulted in strong foaming (pH=1). The resulting precipitate was filtered off with suction, washed with a little water until neutral and dried at 60° C. overnight. This gave 284 g of a beige powder, corresponding to a yield of 89% of theory.

Workup

  1. customgiving, without any change in temperature
  2. temperatureunder reflux (internal temperature 74° C.)
  3. customa stirrable white slurry was formed
  4. temperatureAfter cooling to 54° C.
  5. temperaturethe mixture was then again heated at the boil
  6. temperatureunder reflux
  7. waitAfter 15 hours
  8. temperature40 minutes (conversion monitored by GC) at reflux (85° C.)
  9. temperatureAfter a further 5 hours under reflux at 86° C. (conversion
  10. additionwere added dropwise at 86° C.
  11. temperature(reflux) over a period of 15 minutes
  12. temperatureat reflux at this temperature for a further 4 hours, during which a gentle evolution of waste gas
  13. customUndissolved particles were then substantially decanted off over a Nutsche
  14. filtrationfiltered off with suction over the Nutsche
  15. concentrationThe resulting two-phase filtrate was concentrated at 20 mbar (1350 ml of distillate)
  16. additiondiluted again with 1000 ml of water
  17. extractionOrganic impurities were extracted
  18. concentrationon concentration
  19. customa rotary evaporator) and the aqueous phase
  20. additionwas poured into 920 g of 24% by weight strength aqueous sulphuric acid (18-24° C.), which
  21. customresulted in strong foaming (pH=1)
  22. filtrationThe resulting precipitate was filtered off with suction
  23. washwashed with a little water until neutral and
  24. customdried at 60° C. overnight

Sources & evidence

ORD record
ord-4e7e4d55110c43f9aaeb3292b691a18c
Source dataset
uspto-grants-2002_05
Patent number
US06395921B1

Reaction notes

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