Sodium hydride → Ethyl 5-trifluoromethyl-1-[(thiazol-2-yl)]methyl-1H-indole-2-carboxylate

HRID 1911250Notes

Reaction equation

HRID 1911250 reaction equation
[H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2.Cl[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:20][C:4]([F:19])([F:3])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2

Participants

7

Reactant 3

HCID 24758Sodium hydrideHCID 140908642-(Chloromethyl)-1,3-thiazoleHCID 17389890Ethyl 5-(trifluoromethyl)-1H-indole-2-carboxylate

Product 1

HCID 66888728Ethyl 5-trifluoromethyl-1-[(thiazol-2-yl)]methyl-1H-indole-2-carboxylateYield 56.6%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a suspension of 87 mg (1.983 mmol) of sodium hydride (55%) in 10 mL of dry DMF, maintained under an inert atmosphere, are added dropwise, at room temperature, 340 mg (1.322 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate in 5 mL of dry DMF. The reaction mixture is stirred at 50° C. for 1 hour. A solution of 265 mg (1.983 mmol) of 2-(chloromethyl)thiazole, prepared according to the protocol described in the preceding step, in 10 mL of THF is then added dropwise, at 0° C. The reaction mixture is then stirred for 20 hours at room temperature, and then diluted with 100 mL of ethyl acetate. The aqueous phase is extracted with 30 mL of ethyl acetate. The combined organic phases are washed successively with saturated aqueous sodium hydrogen carbonate solution, with water, with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 265 mg of the expected product are isolated in the form of a colourless oil.

Workup

  1. temperaturemaintained under an inert atmosphere
  2. additionare added dropwise, at room temperature
  3. additionis then added dropwise, at 0° C
  4. stirringThe reaction mixture is then stirred for 20 hours at room temperature
  5. extractionThe aqueous phase is extracted with 30 mL of ethyl acetate
  6. washThe combined organic phases are washed successively with saturated aqueous sodium hydrogen carbonate solution, with water, with saturated aqueous sodium chloride solution
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe resulting oil is purified by chromatography on a column of silica
  11. washeluting with a mixture of heptane and ethyl acetate

Sources & evidence

ORD record
ord-ae7a131183194fc4aa40cce224650c6e
Source dataset
uspto-grants-2013_12
Patent number
US08604050B2

Reaction notes

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