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

HRID 1616818Notes

Reaction equation

HRID 1616818 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].[NH2:18][CH2:19][C:20]1[C:21](=[O:27])[NH:22][CH:23]=[CH:24][C:25]=1[CH3:26].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>C(Cl)(Cl)Cl.ClCCl.O.CS(C)=O>[NH3:7].[CH3:11][OH:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:18][CH2:19][C:20]3[C:21](=[O:27])[NH:22][CH:23]=[CH:24][C:25]=3[CH3:26])=[O:13])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16]

Participants

11

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 678159882(1H)-Pyridinone, 3-(aminomethyl)-4-methyl-HCID 678162465-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid

Product 2

HCID 21705897Ammonia methanolYield 10%HCID 678119545-bromo-1-methyl-3-(1-methylethyl)-N-[(4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamideYield 118.3%

Reagents, catalysts & solvents 4

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Procedure

A 20 mL, oven dried vial was charged with 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (0.10 g, 0.338 mmol), 3-(aminomethyl)-4-methyl-2(1H)-pyridinone (0.088 g, 0.506 mmol), 1-hydroxy-7-azabenzotriazole (0.069 g, 0.506 mmol) and EDC (0.097 g, 0.506 mmol). To the mixture was added dimethyl sulfoxide (DMSO) (3 mL) via syringe, followed by N-methylmorpholine (0.148 mL, 1.351 mmol). The mixture was capped and stirred at RT overnight. The reaction was poured into 60 mL water and the resultant mixture stirred for 10 min, then placed in a freezer for 10 min. The solids were filtered, washed with water (10 mL), air dried for 5 min, and placed in a vacuum oven (40° C.). The solid was dissolved in DCM/MeOH and absorbed onto silica gel and concentrated in vacuo to dryness. Purification by column chromatography (12 g Isco GOLD silica column; Gradient B: 5-85%, A: dichloromethane, B: 10% 2 M ammonia/methanol in chloroform) gave 5-bromo-1-methyl-3-(1-methylethyl)-N-[(4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (85 mg, 0.200 mmol, 59.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=6.82 Hz, 6H) 2.26 (s, 3H) 3.03-3.17 (m, 1H) 3.64 (s, 3H) 4.34 (d, J=4.80 Hz, 2H) 6.05 (d, J=6.57 Hz, 1H) 7.09 (d, J=1.77 Hz, 1H) 7.14 (s, 1H) 7.22 (d, J=6.82 Hz, 1H) 7.75 (d, J=1.77 Hz, 1H) 8.57 (t, J=4.80 Hz, 1H) 11.48 (br. s., 1H). MS (ES) [M+H]+ 415.9.

Workup

  1. customA 20 mL, oven dried vial
  2. customThe mixture was capped
  3. waitplaced in a freezer for 10 min
  4. filtrationThe solids were filtered
  5. washwashed with water (10 mL), air
  6. customdried for 5 min
  7. customplaced in a vacuum oven (40° C.)
  8. dissolutionThe solid was dissolved in DCM/MeOH
  9. customabsorbed onto silica gel
  10. concentrationconcentrated in vacuo to dryness
  11. customPurification by column chromatography (12 g Isco GOLD silica column

Sources & evidence

ORD record
ord-8d2fc664f8ff4dd29d8f1f6407fd37ce
Source dataset
uspto-grants-2014_07
Patent number
US08765792B2

Reaction notes

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