Hydrochloric Acid → (5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester

HRID 402903Notes

Reaction equation

HRID 402903 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:2].Cl.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:19]2[C:18](=[CH:17][CH:16]=[C:15]([CH3:23])[CH:20]=2)[NH:21][C:7]=1[C:8]([F:11])([F:10])[F:9])[CH3:2]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 125044-Methylphenylhydrazine monohydrochlorideHCID 13379932Ethyl 5,5,5-trifluoro-4-oxopentanoate

Product 1

HCID 59192032(5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl esterYield 60%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+.

Workup

  1. temperatureheated
  2. temperatureat reflux for 18 h under an argon atmosphere
  3. temperatureAfter cooling to room temperature the reaction mixture
  4. concentrationis concentrated by rotary evaporation
  5. customThe residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc
  6. customThe layers are separated
  7. extractionthe aqueous phase is extracted with twice with EtOAc
  8. washThe combined organic layers are washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated at reduced pressure
  12. customto afford a brown oil
  13. customPurification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

Sources & evidence

ORD record
ord-0b640b139cc54c7080546b53a776c645
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Reaction notes

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