1,2-Dichloroethane → N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxamide

HRID 1616807Notes

Reaction equation

HRID 1616807 reaction equation
[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]3[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:21]([CH3:23])[CH3:22])=[CH:3]1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:11]([C:9]1[CH:8]=[C:7]([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:21]([CH3:22])[CH3:23])=[O:13]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 70638443-(Aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-oneHCID 678173771-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid

Product 1

HCID 67814389N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxamideYield 38.4%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

To a 20 mL vial was added 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid (0.10 g, 0.324 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.098 g, 0.519 mmol), 1-hydroxy-7-azabenzotriazole (0.088 g, 0.649 mmol) and EDC (0.124 g, 0.649 mmol). The reagents were diluted with DMSO (3 mL) and N-methylmorpholine (0.178 mL, 1.621 mmol). The mixture was stirred overnight, then slowly poured into ice-water (50 mL). The mixture was stirred for 10 min, then allowed to sit for 10 min. The mixture was then extracted with EtOAc (2×) and the combined organics washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with MTBE and the resulting solid dried in a vac oven at 45° C. for 4 h. Purified the solid by HPLC (Gilson; Sunfire 30×75 mm column; Gradient B: 10-65%; A: water+0.1% TFA; B: CH3CN+0.1% TFA). The residue was dissolved in 10% MeOH/DCM and treated with Silicycle carbonate resin (0.65 g) at 37° C. for 15 min. The mixture was allowed to cool to RT and was filtered through Celite. Concentrated in vacuo to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxamide (55 mg, 37.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.11 (s, 3H) 2.24 (s, 3H) 3.16-3.28 (m, 1H) 3.33 (s, 3H) 3.68 (s, 3H) 4.36 (d, J=5.05 Hz, 2H) 5.87 (s, 1H) 7.11 (s, 1H) 7.28-7.37 (m, 2H) 7.86 (d, J=1.77 Hz, 1H) 7.98 (dd, J=8.08, 2.53 Hz, 1H) 8.50 (t, J=4.93 Hz, 1H) 8.77 (d, J=2.27 Hz, 1H) 11.50 (s, 1H). MS (ES) [M+H]+ 443.2.

Workup

  1. stirringThe mixture was stirred for 10 min
  2. waitto sit for 10 min
  3. extractionThe mixture was then extracted with EtOAc (2×)
  4. washthe combined organics washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe residue was triturated with MTBE
  8. customthe resulting solid dried in a vac oven at 45° C. for 4 h
  9. customPurified the solid by HPLC (Gilson
  10. dissolutionThe residue was dissolved in 10% MeOH/DCM
  11. additiontreated with Silicycle carbonate resin (0.65 g) at 37° C. for 15 min
  12. filtrationwas filtered through Celite
  13. concentrationConcentrated in vacuo

Sources & evidence

ORD record
ord-ae569438f3154a05aaf2aa4bf5f248af
Source dataset
uspto-grants-2014_07
Patent number
US08765792B2

Reaction notes

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