1,4-Dioxane → 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

HRID 1524382Notes

Reaction equation

HRID 1524382 reaction equation
Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][N:32]1[C:36]([C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=2B(O)O)=[CH:35][CH:34]=[N:33]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][N:14]([C:15]1[S:19][N:18]=[CH:17][N:16]=1)[S:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:38]3[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:44])[F:45])=[CH:42][C:37]=3[C:36]3[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=3)=[CH:3][NH:4]2)=[CH:9][CH:8]=1)(=[O:12])=[O:13]

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 71258947(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid2×HCID 712592863-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

Product 1

HCID 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-sulfonamideYield 80.5%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A vial was charged with 3-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (324 mg, 0.636 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (223 mg, 0.827 mmol), potassium phosphate (405 mg, 1.908 mmol), and Pd(AmPhos)2Cl2 (22.52 mg, 0.032 mmol), 1,4-dioxane (2.4 mL), and water (0.8 mL). The vial was flushed with Ar, sealed, and heated in a microwave reactor to 90° C. for 40 min. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (50 to 100% EtOAc/Heptane) to afford 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 (335.1 mg, 0.512 mmol, 80% yield) as a yellow foam that was about 90% pure as assessed by NMR. 1H NMR (400 MHz, DMSO-d6) δ=11.92 (d, J=2.4 Hz, 1 H), 8.34 (s, 1 H), 8.00 (dd, J=0.4, 1.8 Hz, 1 H), 7.95-7.87 (m, 2 H), 7.79-7.76 (m, 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.49 (dd, J=1.9, 8.6 Hz, 1 H), 7.41 (d, J=1.9 Hz, 1 H), 7.20 (d, J=2.7 Hz, 1 H), 6.92 (d, J=8.4 Hz, 1 H), 6.45 (d, J=2.4 Hz, 1 H), 6.40-6.34 (m, 2H), 5.09 (s, 2 H), 3.72 (s, 3 H), 3.68 (s, 3 H), 3.19 (s, 3 H). m/z (ESI) 655.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar
  2. customsealed
  3. additionThe reaction mixture was diluted with water
  4. extractionextracted with EtOAc (2×)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by chromatography on silica gel (50 to 100% EtOAc/Heptane)

Sources & evidence

ORD record
ord-8048f89bad0a452f92a2911f08e7cd65
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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