Ethanol → 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid

HRID 1673002Notes

Reaction equation

HRID 1673002 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](CC#N)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[OH-:20].[K+].[CH2:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:23][C:22]([OH:20])=[O:24])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1

Participants

4

Reactant 3

HCID 702EthanolHCID 14797Potassium HydroxideHCID 592402732-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetonitrile

Product 1

HCID 592399932-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid

Procedure

Into a 250 mL round bottom flask was weighed 2.3 g of crude 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetonitrile (8.0 mmol). To this was added 40 mL of ethanol and 2.5 g of KOH (44 mmol). The resulting mixture was heated to reflux. After 17 hours at reflux the reaction was cooled and concentrated in vacuo to remove most of the ethanol. The resulting dark oil was taken up in H2O and EtOAc and acidified by the addition of 3N aqueous HCl. The acidic aqueous was extracted with EtOAc (3×), the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the crude acid as a dark oil. The crude product was purified by silica gel flash chromatography on an 80 g column using gradient elution from 0% to 40% acetonitrile/CH2Cl2 and collected by monitoring the UV response at 240 nm. Appropriate fractions were combined and concentrated in vacuo to afford 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid as a dark glass. The product was not completely pure and was taken up in 1N NaOH and Et2O. The ether layer was extracted with 1N NaOH (1×) and the combined basic aqueous layers were extracted with Et2O (1×). The basic layer was acidified by the addition of concentrated HCl and was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid as a yellow oil that partially solidified after standing under vacuum overnight: yield 1.5 g (61% yield); 1H NMR (400 MHz, CDCl3): δ 7.58-7.54 (m, 1H), 7.52-7.39 (m, 3H), 6.73 (s, 1H), 3.80-3.45 (broad hump, 2H); MS (ESI) m/z 305.0 [M+H]+.

Workup

  1. customInto a 250 mL round bottom flask was weighed
  2. temperatureThe resulting mixture was heated to reflux
  3. temperatureAfter 17 hours at reflux the reaction
  4. temperaturewas cooled
  5. concentrationconcentrated in vacuo
  6. customto remove most of the ethanol
  7. additionEtOAc and acidified by the addition of 3N aqueous HCl
  8. extractionThe acidic aqueous was extracted with EtOAc (3×)
  9. washthe combined organic extracts were washed with brine
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto afford the crude acid as a dark oil
  14. customThe crude product was purified by silica gel flash chromatography on an 80 g column
  15. washelution from 0% to 40% acetonitrile/CH2Cl2
  16. customcollected
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-9c0c14d5d08b4b6bba9ff007095a380a
Source dataset
uspto-grants-2011_08
Patent number
US07998995B2

Reaction notes

Loading…