Isopropyl iodide → 1-isopropyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

HRID 1524405Notes

Reaction equation

HRID 1524405 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].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:53]([CH3:55])[CH3:54].C(Cl)(=O)C>O.C(#N)C>[CH:53]([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:8])=[O:9])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)([CH3:55])[CH3:54]

Participants

7

Reactant 4

HCID 6362Isopropyl iodideHCID 6367Acetyl chlorideHCID 10796Cesium carbonateHCID 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 712638391-isopropyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamideYield 80%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
70 °C

Procedure

A vial 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) (57.4 mg, 0.088 mmol), cesium carbonate (86 mg, 0.263 mmol), acetonitrile (0.5 mL), and 2-iodopropane (26.3 μl, 0.263 mmol). The vial was sealed and heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up on in MeOH (1 mL), then acetyl chloride (31.2 μl, 0.438 mmol) was added. After stirring for 1 h, the mixture was concentrated in vacuo. The residue was taken up in a solution of 2N ammonia in methanol, and the resulting slurry was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-isopropyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (38.52 mg, 0.070 mmol, 80% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.36 (s, 1 H), 8.00 (d, J=1.5 Hz, 1 H), 7.96-7.89 (m, 2 H), 7.79-7.75 (m, 1H), 7.70 (d, J=8.5 Hz, 1 H), 7.48 (dd, J=1.7, 8.5 Hz, 1 H), 7.44 (d, J=1.9 Hz, 1 H), 7.09 (s, 1 H), 6.42 (d, J=1.9 Hz, 1 H), 4.86 (td, J=6.5, 13.2 Hz, 1 H), 1.33 (d, J=6.6 Hz, 6 H). m/z (ESI) 547.2 (M+H)+.

Workup

  1. customThe vial was sealed
  2. temperatureThe mixture was cooled to room temperature
  3. extractionextracted with EtOAc (2×)
  4. dry with materialThe combined organic extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. concentrationthe mixture was concentrated in vacuo
  8. concentrationthe resulting slurry was concentrated in vacuo
  9. customThe crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-48802b88456a4687a6c067ab26f00f3c
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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