Acetyl chloride → (1-acetyl-5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester

HRID 402902Notes

Reaction equation

HRID 402902 reaction equation
[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[C:16]([F:19])([F:18])[F:17])[CH3:2].[H-].[Na+].[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:23](=[O:25])[CH3:24])[C:7]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 24758Sodium hydrideHCID 59192032(5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester

Product 1

HCID 59192042(1-acetyl-5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl esterYield 51.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (4.90 g, 17.2 mmol) in DMF (25 mL) is added a suspension of 60% NaH in mineral oil (824 mg, 20.6 mmol). The reaction mixture is stirred for 1 h at room temperature. After cooling to 0° C. acetylchloride (1.84 mL, 25.8 mmol) is added dropwise. The resulting reaction mixture is stirred for 1 h at room temperature, quenched with an aqueous saturated NH4Cl solution and partitioned between water and EtOAc. The layers are separated and the aqueous phase is extracted 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, cyclohexane/EtOAc 95:5) affords the title compound as a yellow solid (2.89 g, 8.83 mmol, 51%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.75 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.91 (q, J=2.2 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 345 (M(C16H16F3NO3)+H2O)+.

Workup

  1. additionis added dropwise
  2. customThe resulting reaction mixture
  3. stirringis stirred for 1 h at room temperature
  4. customquenched with an aqueous saturated NH4Cl solution
  5. custompartitioned between water and EtOAc
  6. customThe layers are separated
  7. extractionthe aqueous phase is extracted 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, cyclohexane/EtOAc 95:5)

Sources & evidence

ORD record
ord-c9f76b3a3c144484ac03e389f8334afd
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Reaction notes

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