Ethyl Acetate → ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

HRID 1941882Notes

Reaction equation

HRID 1941882 reaction equation
[NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O/[CH:12]=[C:13](/[C:19](=O)[C:20]([F:23])([F:22])[F:21])\[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Na+].O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:19]([C:20]([F:21])([F:22])[F:23])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[N:2]1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 786452-HydrazinopyridineHCID 516892Sodium BicarbonateHCID 2737179Ethyl 2-(ethoxymethylene)-4,4,4-trifluoroacetoacetate2×

Product 1

HCID 58504358ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylateYield 81.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-33.5 °C

Procedure

A solution of 2-hydrazinopyridine (5 g, 45.8 mmol) in THF (200 mL) under nitrogen was cooled in a dry ice/isopropanol bath to −34° C. A solution of (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (11 g, 45.8 mmol) in THF (73 mL) was added in a slow stream over 25 minutes, with nitrogen flush. During the addition, the internal reaction temperature averaged −34° C., and never exceeded −31° C. After completion of the addition, stirring at −33.5° C. was continued for ˜40 min. Additional (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.89 mL, 0.10 eq) was added and stirring at −30° C. was continued for 11 min. EtOAc (270 mL) was added along with sat. aq. NaHCO3 solution (250 mL) and brine (20 mL). The layers were separated and the organic layer was washed with sat. aq. NaHCO3 solution, brine, then dried (Na2SO4) and concentrated under vacuum to yield an orange viscous oil. Flash chromatography on silica gel yielded ethyl 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (10.62 g) as a yellow solid. The compound had an HPLC retention time=2.5 min.−Column: YMC COMBISCREEN® ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.1.

Workup

  1. customflush
  2. additionDuring the addition
  3. customaveraged −34° C.
  4. customnever exceeded −31° C
  5. additionAfter completion of the addition
  6. stirringstirring at −30° C.
  7. waitwas continued for 11 min
  8. customThe layers were separated
  9. washthe organic layer was washed with sat. aq. NaHCO3 solution, brine
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated under vacuum
  12. customto yield an orange viscous oil

Sources & evidence

ORD record
ord-796b1487900045a481af3589b1ee17da
Source dataset
uspto-grants-2013_03
Patent number
US08389509B2

Reaction notes

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