Acetic Acid → 5-(5-Ethoxycarbonylpentyl)imidazo[1,5-a]pyridine

HRID 326145Notes

Reaction equation

HRID 326145 reaction equation
[CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21](OCC)([O:25]CC)[O:22][CH2:23][CH3:24].C(O)(=O)C>O1CCCC1>[CH2:23]([O:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:25])[CH3:24]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 122109855-Methylimidazo(1,5-a)pyridineHCID 132061375-Bromo-1,1,1-triethoxypentaneHCID 178418339Butyllithium3×

Product 1

HCID 132061385-(5-Ethoxycarbonylpentyl)imidazo[1,5-a]pyridine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

5-Methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975), 424.7 g]is charged into a 12 liter flask equipped with mechanical stirrer, thermometer and nitrogen atmosphere. Dry tetrahydrofuran (THF, 3,000 ml) is charged into the flask and the resulting solution is cooled to -65° in a dry ice/acetone bath. n-Butyllithium (1.0 mole, 2.4 N in hexane) is poured into the flask all at once under a nitrogen atmosphere. The temperature rises to -32°. The mixture is recooled to -50° and a second mole of n-butyllithium is charged in the same manner. A second temperature rise occurs and after again cooling to -50°, a third mole of the n-butyl-lithium is charged into the reactor. The reaction mixture is then stirred for twenty minutes, the temperature drops to -65°. To this stirring solution a cold (-67°) solution of 5-bromo-1,1,1-triethoxypentane (606.9 g) in 500 ml of THF is added as rapidly as possible, raising the temperature to -25°. The reaction mixture is then warmed to -15° and stirred for 2 hours. Acetic acid (50 ml) is added and most of the solvent is removed under vacuum. The residue is taken up in 2,000 ml of ethyl ether; acetic acid (100 ml), and 12 N HCl (100 ml) are added while the reaction mixture is cooled to 0°. After 15 to 20 minutes, ice-cold 7.5 N ammonium hydroxide (1000 ml) is added. The organic phase is separated and the aqueous is washed again with ethyl ether (500 ml). The pH of the aqueous is adjusted to 9 with ammonium hydroxide and extracted again wth ethyl ether (500 ml). The combined ether extracts are washed with a dilute sodium chloride solution basified to pH 13-14 with potassium hydroxide. The ether extract is treated with charcoal and magnesium sulfate. The mixture is filtered and evaporated to give a dark oil which is dried at 2mm Hg. The oil is distilled under high vaccuum to give 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine of Example 1, boiling at 220°/0.2 mm Hg.

Workup

  1. customequipped with mechanical stirrer
  2. temperaturethe resulting solution is cooled to -65° in a dry ice/acetone bath
  3. customrises to -32°
  4. customis recooled to -50°
  5. temperatureafter again cooling to -50°
  6. customdrops to -65°
  7. temperatureraising the temperature to -25°
  8. temperatureThe reaction mixture is then warmed to -15°
  9. stirringstirred for 2 hours
  10. customis removed under vacuum
  11. additionacetic acid (100 ml), and 12 N HCl (100 ml) are added while the reaction mixture
  12. temperatureis cooled to 0°
  13. additionice-cold 7.5 N ammonium hydroxide (1000 ml) is added
  14. customThe organic phase is separated
  15. washthe aqueous is washed again with ethyl ether (500 ml)
  16. extractionextracted again wth ethyl ether (500 ml)
  17. washThe combined ether extracts are washed with a dilute sodium chloride solution
  18. extractionThe ether extract
  19. additionis treated with charcoal and magnesium sulfate
  20. filtrationThe mixture is filtered
  21. customevaporated
  22. customto give a dark oil which
  23. customis dried at 2mm Hg
  24. distillationThe oil is distilled under high vaccuum

Sources & evidence

ORD record
ord-b3da207cd96041a9a4859ddf3a6610b7
Source dataset
uspto-grants-1984_04
Patent number
US04444775

Reaction notes

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