1H-1,2,4-Triazole → 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine

HRID 2374881Notes

Reaction equation

HRID 2374881 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:29]=[CH:30][CH:31]=1

Participants

5

Reactant 3

HCID 92571H-1,2,4-TriazoleHCID 24813Phosphorus oxychlorideHCID 587119543-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide2×

Product 1

HCID 112135557-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amineYield 48.9%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution of 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 18) (490 mg, 1.0 mmol) and 1,2,4-triazole (210 mg, 3.0 mmol) in pyridine (10 mL) was added phosphorus oxychloride (0.14 mL, 1.5 mmol). The mixture was stirred at room temperature for 24 hours. The excess phosphorus oxychloride was quenched with methanol and ammonium hydroxide. The product was extracted into ethyl acetate (100 mL) and washed with 0.1N hydrochloric acid (3×50 mL). The solution was dried with magnesium sulfate and filtered. Silica gel (2.5 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (25:75) to ethyl acetate:hexanes (75:25) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (0.23 g) as a yellow solid. 1H NMR (CD3OD): δ9.01 (s, 1H) 8.51 (dd, J=1.9, 1.6 Hz, 1H), 8.33 (ddd, J=7.9, 1.4, 1.1 Hz, 1H), 7.57 (ddd, J=7.9, 1.9, 1.1 Hz, 1H), 7.38 (dd, J=8.1, 7.9 Hz, 1H), 6.99 (s, 2H), 3.76 (s, 6H), 3.75 (s, 3H), 2.56 (s, 3H). MS m/z 470, 472 (M+1, M+3).

Workup

  1. customThe excess phosphorus oxychloride was quenched with methanol and ammonium hydroxide
  2. extractionThe product was extracted into ethyl acetate (100 mL)
  3. washwashed with 0.1N hydrochloric acid (3×50 mL)
  4. dry with materialThe solution was dried with magnesium sulfate
  5. filtrationfiltered
  6. additionSilica gel (2.5 g) was added
  7. customfollowed by evaporation of the volatiles under reduced pressure
  8. washsubjected to a gradient elution
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-e57995ff5262495f949b4e2532746443
Source dataset
uspto-grants-2008_12
Patent number
US07462614B2

Reaction notes

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