5-Methylpyrazin-2-amine → N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrazine-2-carboxamide

HRID 1253619Notes

Reaction equation

HRID 1253619 reaction equation
[CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl-].C[Al+]C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:18]=[CH:19][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[N:21][CH:22]=1)=[O:16]>COC>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[CH:22]=[N:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](=[O:35])[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:25]=2)=[CH:19][N:18]=1)=[O:16]

Participants

5

Reactant 3

HCID 3132155-Methylpyrazin-2-amineHCID 16686359Dimethylalumanylium chlorideHCID 59483311Ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate

Product 1

HCID 46916741N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrazine-2-carboxamideYield 72%

Reagents, catalysts & solvents 1

HCID 8254Dimethyl EtherSolvent2×

Conditions

Temperature
0 °C

Procedure

5-methyl-2-aminopyrazine (6.8 g, 63 mmol) was taken up in 70 mL of dimethylether and cooled to 0° C. Dimethyaluminium chloride (131 mmol, 1 M in hexane) was added dropwise. The resulting mixture was warmed up to ambient temperature and stirred for 30 min. Ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-1d: 10.1 g, 27.3 mmol) in dimethylether (70 mL) was then added to the activated amine solution via canula. The combined solution was heated to reflux overnight. The reaction was cooled on ice and slowly quenched by the dropwise addition of aqueous Rochelle's salt (concentrated, 100 mL). The mixture was stirred for 20 minutes. The mixture was separated. Organic layer was washed with aqueous Rochelle's salt (30 ml), 1N HCl (30 ml), brine (30 ml), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, gradient of ethyl acetate from 50-100% in heptane) to give desired N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrazine-2-carboxamide (1: 8.5 gram 72%).

Workup

  1. temperatureThe resulting mixture was warmed up to ambient temperature
  2. temperatureThe combined solution was heated
  3. temperatureto reflux overnight
  4. temperatureThe reaction was cooled on ice
  5. customslowly quenched by the dropwise addition of aqueous Rochelle's salt (concentrated, 100 mL)
  6. stirringThe mixture was stirred for 20 minutes
  7. customThe mixture was separated
  8. washOrganic layer was washed with aqueous Rochelle's salt (30 ml), 1N HCl (30 ml), brine (30 ml)
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by column chromatography (silica gel, gradient of ethyl acetate from 50-100% in heptane)

Sources & evidence

ORD record
ord-2427385916184c34a590f9be8a8b5ee4
Source dataset
uspto-grants-2013_06
Patent number
US08455496B2

Reaction notes

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