Potassium Phosphate, Tribasic → 3-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

HRID 1524412Notes

Reaction equation

HRID 1524412 reaction equation
[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[C:41]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:42]=1[C:43]#[N:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C=O)C>[C:43]([C:42]1[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:41]=1[C:14]1[C:13]2[C:17](=[CH:18][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=3[O:2][CH3:1])[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[N:16]([CH3:19])[CH:15]=1)#[N:44]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 122239802-Bromo-5-(trifluoromethyl)benzonitrileHCID 71259251N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

Product 1

HCID 712593943-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.075 g, 0.131 mmol), 2-bromo-5-(trifluoromethyl)benzonitrile (0.082 g, 0.329 mmol). potassium phosphate (0.098 g, 0.460 mmol), and PdCl2(dppf)-CH2Cl2 (10.74 mg, 0.013 mmol). DMF (0.876 ml) was added, and the vial was flushed with Ar, sealed, and heated to 85° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (0 to 100% EtOAc/Heptane) to give 3-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a light yellow solid. The solid was dissolved in DCM (0.5 ml) and TFA (0.5 ml, 6.49 mmol), and the resulting mixture was stirred for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 3-(2-cyano-4-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.022 g, 0.047 mmol, 36.1% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.44 (s, 1 H), 8.42 (s, 1 H), 8.17 (s, 1 H), 8.14-8.10 (m, 1 H), 8.07 (d, J=1.2 Hz, 1 H), 7.95 (d, J=8.1 Hz, 1 H), 7.83 (d, J=8.5 Hz, 1 H), 7.60 (dd, J=1.6, 8.5 Hz, 1 H), 4.01 (s, 3 H). m/z (ESI) 464.0 (M+H)+.

Workup

  1. customthe vial was flushed with Ar
  2. customsealed
  3. additionThe reaction was diluted with ethyl acetate
  4. washwashed with water
  5. extractionThe aqueous layer was extracted with ethyl acetate
  6. washthe combined organic layers were washed with brine
  7. dry with materialdried with sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe material was purified via column chromatography (0 to 100% EtOAc/Heptane)

Sources & evidence

ORD record
ord-a8ba152cde8246c2a381cd044b627491
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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