Triethylamine → 5-(2-fluorophenyl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine

HRID 931337Notes

Reaction equation

HRID 931337 reaction equation
[NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32](=O)[NH:31][CH:30]=[N:29]2>C(#N)C>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[N:31][CH:30]=[N:29]2

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 92571H-1,2,4-TriazoleHCID 24813Phosphorus oxychlorideHCID 1369841475-(2-fluorophenyl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Product 1

HCID 1176784165-(2-fluorophenyl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

1H-1,2,4-Triazole (15.1 g, 219 mmol) in acetonitrile (220 mL) was cooled to 0° C. and treated slowly with phosphorus oxychloride (5.99 mL, 65.4 mmol). After 10 minutes, triethylamine (36.5 mL, 262 mmol) was slowly added; the reaction was stirred for an additional 10 minutes at 0° C., then slowly warmed to room temperature over 15 minutes. C5 (5.33 g, 21.8 mmol) was added to the reaction mixture and stirring was continued at room temperature for 2 hours. After concentration in vacuo, the residue was diluted with ethyl acetate (˜250 mL) and poured into ice-cold stirring aqueous potassium phosphate solution (25%, 250 mL). After stirring for 10 minutes, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel chromatography (small plug of silica gel employed; Eluent: 2:1 heptane/ethyl acetate) provided the product as a bright yellow solid. Yield: 6.50 g, 21.8 mmol, 100%. LCMS m/z 296.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 7.74 (ddd, J=7.6, 7.4, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.26 (ddd, J=7.6, 7.5, 1.2 Hz, 1H), 6.88 (ddd, J=10.2, 8.3, 1.1 Hz, 1H), 2.87 (s, 3H).

Workup

  1. temperatureslowly warmed to room temperature over 15 minutes
  2. stirringstirring
  3. waitwas continued at room temperature for 2 hours
  4. concentrationAfter concentration in vacuo
  5. additionthe residue was diluted with ethyl acetate (˜250 mL)
  6. additionpoured into ice-cold stirring aqueous potassium phosphate solution (25%, 250 mL)
  7. stirringAfter stirring for 10 minutes
  8. customthe layers were separated
  9. extractionthe aqueous layer was extracted with ethyl acetate
  10. dry with materialThe combined organic layers were dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customPurification via silica gel chromatography (small plug of silica gel employed; Eluent: 2:1 heptane/ethyl acetate)

Sources & evidence

ORD record
ord-a4baf53adeda4066879dff542ff63636
Source dataset
uspto-grants-2016_03
Patent number
US09296761B2

Reaction notes

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