Hydrochloric Acid → Ethyl 3-cyclopropyl-2,2-difluoropropanoate

HRID 2190959Notes

Reaction equation

HRID 2190959 reaction equation
F[C:2](F)(F)C(O)=O.ICI.[F:11][C:12]([F:21])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>ClCCl.[Cu].[Zn]>[CH:19]1([CH2:18][C:12]([F:21])([F:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:20]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6346DiiodomethaneHCID 6422Trifluoroacetic acidHCID 14049931Ethyl 2,2-difluoropent-4-enoate

Product 1

HCID 50997080Ethyl 3-cyclopropyl-2,2-difluoropropanoate

Reagents, catalysts & solvents 2

HCID 10290809Zinc copper coupleCatalyst3×HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
2.5 °C

Procedure

Zinc-copper (Zn—Cu) couple (1.6 Kg, 800 mol %) and dichloromethane (7.5 L) was charged into a dry 20.0 L, 4-neck round bottomed flask, fitted with an over head stirrer, a thermo socket and a condenser under a nitrogen atmosphere. Trifluoroacetic acid (235 mL, 100 mol %) was added to the above Zn—Cu couple at ambient temperature via addition funnel over 30 minutes. Diiodomethane (860 mL; 2.86 Kg; 10.7 mol; 352 mol %) was added to above the Zn—Cu couple at ambient temperature via addition funnel over 1.5 hours. The reaction temperature was raised to reflux and then ethyl 2,2-difluoropent-4-enoate (500 g; 3.05 mol) in dichloromethane (500 mL) was added slowly via addition funnel over 30 minutes at reflux. The reaction temperature was maintained for 40-60 hours at reflux. Progress of the reaction was monitored by GC analysis which showed about 93% conversion to product based on relative area % of the peaks corresponding to product and starting material. The reaction mass was cooled to 0-5° C. and 5% dilute hydrochloric acid (500 mL) was added then the solution was filtered and washed with dichloromethane (1500 mL). The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) followed by a solution of brine (1000 mL). The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg to provide crude ethyl 3-cyclopropyl-2,2-difluoropropanoate (740 g), which was 79% pure by GC analysis. The crude product was then subjected to an oxidative work-up as described below to remove residual starting material (5% by area as determined by GC analysis).

Workup

  1. customfitted with an over head stirrer
  2. temperatureThe reaction temperature was raised
  3. temperatureto reflux
  4. temperatureat reflux
  5. temperatureThe reaction temperature was maintained for 40-60 hours
  6. temperatureat reflux
  7. filtrationthe solution was filtered
  8. washwashed with dichloromethane (1500 mL)
  9. washThe filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL)
  10. concentrationThe organic layer was concentrated under vacuum at 35° C./260-360 mm Hg

Sources & evidence

ORD record
ord-62f99724f4a74399a094cd9a33e93216
Source dataset
uspto-grants-2012_12
Patent number
US08324417B2

Reaction notes

Loading…