Nitrogen → 1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(methylsulfonyl)-1H-indole-4-carboxamide

HRID 1476948Notes

Reaction equation

HRID 1476948 reaction equation
N#N.[CH3:3][S:4]([O-:6])=[O:5].[Na+].C[N:9](C)CCN.Br[C:15]1[CH:16]=[C:17]([C:28]([NH:30][CH2:31][C:32]2[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[CH:23]=1>O.CO.C(Cl)(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.ClCCl.CS(C)=O>[NH3:9].[CH:24]1([N:21]2[C:22]3[CH:23]=[C:15]([S:4]([CH3:3])(=[O:6])=[O:5])[CH:16]=[C:17]([C:28]([NH:30][CH2:31][C:32]4[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=4[CH3:38])=[O:29])[C:18]=3[C:19]([CH3:27])=[CH:20]2)[CH2:26][CH2:25]1

Participants

12

Reactant 4

HCID 947NitrogenHCID 66053N,N-DimethylethylenediamineHCID 2733271Sodium methanesulfinateHCID 674641766-bromo-1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-indole-4-carboxamide

Product 2

HCID 222AmmoniaHCID 674686391-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(methylsulfonyl)-1H-indole-4-carboxamideYield 79%

Reagents, catalysts & solvents 6

HCID 2734996copper(II) trifluoromethanesulfonateCatalystHCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

To a vial under a stream of N2 was added copper(II) trifluoromethanesulfonate (0.084 g, 0.233 mmol), sodium methanesulfinate (0.056 g, 0.467 mmol), DMSO (1.3 mL), and N,N-dimethyletylene diamine (0.053 mL, 0.490 mmol). The deep blue reaction was stirred for 5 min, then was added 6-bromo-1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-indole-4-carboxamide (0.10 g, 0.233 mmol). The vial was sealed and heated at 120° C. for 3 h, at which time it was diluted with water (50 ml). The mixture was extracted with 30% THF/EtOAc (2×) (needed to warm to break up emulsion). Combined organics, dried over magnesium sulfate, filtered through Celite, and concentrated. Purification of the residue by column chromatography (12 gram Isco GOLD silica column; gradient B:5-85%; A:dichloromethane, B:10% (2 M ammonia in MeOH) in chloroform) provided 1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(methylsulfonyl)-1H-indole-4-carboxamide (83 mg, 0.184 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 8.38 (t, J=5.1 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.46 (dd, J=7.8, 1.3 Hz, 2H), 5.87 (s, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.52 (tt, J=7.0, 3.6 Hz, 1H), 3.20 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 1.09 (m, 2H), 0.96 (m, 2H). MS(ES) [M+H]+ 427.8.

Workup

  1. customThe deep blue reaction
  2. customThe vial was sealed
  3. extractionThe mixture was extracted with 30% THF/EtOAc (2×) (
  4. temperatureto warm
  5. dry with materialCombined organics, dried over magnesium sulfate
  6. filtrationfiltered through Celite
  7. concentrationconcentrated
  8. customPurification of the residue by column chromatography (12 gram Isco GOLD silica column

Sources & evidence

ORD record
ord-75c839ae66bc4fad8b9a4eccac5c493a
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

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