Acetyl chloride → 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

HRID 1524406Notes

Reaction equation

HRID 1524406 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[H-].[Na+].[C:48](OC(=O)C)(=[O:50])[CH3:49].C(Cl)(=O)C>O.CCOC(C)=O.[Cl-].[Na+].O.CN(C=O)C>[C:48]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:9])=[O:8])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)(=[O:50])[CH3:49]

Participants

9

Reactant 4

HCID 6367Acetyl chlorideHCID 7918Acetic AnhydrideHCID 24758Sodium hydrideHCID 71259342N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide2×

Product 1

HCID 712598761-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamideYield 68%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (85.95 mg, 0.131 mmol) and DMF (1.3 mL) to give a clear, light-yellow solution. Sodium hydride (60% in mineral oil) (7.88 mg, 0.197 mmol) was added, and the resulting mixture was stirred for 15 min. Acetic anhydride (24.77 μl, 0.263 mmol) was added dropwise to give a thick slurry. After 15 min of stirring, the mixture was diluted with water, EtOAc, and a small amount of brine. The layers were separated, and the aq. layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL) and treated dropwise with acetyl chloride (46.7 μl, 0.656 mmol) for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in DCM (2 mL) and triethylamine (0.5 mL). The resulting solution was again concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (48.77 mg, 0.089 mmol, 68.0% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.82 (dd, J=0.5, 1.7 Hz, 1 H), 8.42 (s, 1 H), 8.06-7.97 (m, 1 H), 7.93-7.85 (m, 3 H), 7.60 (dd, J=1.8, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.33 (s, 1 H), 6.31 (d, J=1.9 Hz, 1 H), 3.43 (s, 3 H), 2.59 (s, 3 H). m/z (ESI) 547.2 (M+H)+.

Workup

  1. customto give a clear, light-yellow solution
  2. customto give a thick slurry
  3. stirringAfter 15 min of stirring
  4. customThe layers were separated
  5. extractionthe aq. layer was extracted with EtOAc
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in MeOH (1 mL)
  9. concentrationThe reaction mixture was concentrated in vacuo
  10. concentrationThe resulting solution was again concentrated
  11. customthe crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-0f270e66de3c4bebb4812ee73b04ec0c
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

Loading…