Sulfuric Acid → (6-Aminopyridin-3-yl)methanol

HRID 402897Notes

Reaction equation

HRID 402897 reaction equation
S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1.C([O-])([O-])=O.[Na+].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.O>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=1

Participants

8

Reactant 5

HCID 1118Sulfuric AcidHCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 184966-Aminonicotinic acidHCID 21226445Aluminium lithium hydride

Product 1

HCID 2794829(6-Aminopyridin-3-yl)methanolYield 72%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

Concentrated sulfuric acid (0.95 ml, 17.2 mmol, 0.5 equiv) is added to a solution of 6-aminonicotinic acid (5.0 g, 34.4 mmol) in ethanol (50 ml). After heating to reflux for 16 hours, the reaction mixture is carefully poured into a concentrated aqueous Na2CO3 solution. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in anhydrous THF (25 ml). At −60° C., lithium aluminium hydride (2.68 g, 68.6 mmol, 3.0 equiv) is carefully added. The mixture is warmed to 0° C., and then refluxed for 1 hour. After cooling, water (1.5 ml) and 5 N aqueous NaOH solution (1.5 ml) are added. The precipitate is filtered off, and the filtrate is concentrated in vacuo. The residue is purified via flash chromatography (EtOAc I MeOH 95:5) to afford the title compound (2.15 g, 72%). 1H NMR (400 MHz, d6-DMSO): δ=7.82 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.3/2.5 Hz, 1H), 6.40 (dd, J=9.3/1.0 Hz, 1H), 5.77 (br s, 2H), 4.88 (t, J=5.5 Hz, 1H), 4.27 (d, J=5.5 Hz, 2H). MS (ES+): 125 (M+H)+.

Workup

  1. temperatureAfter heating
  2. temperatureto reflux for 16 hours
  3. extractionThe aqueous phase is extracted three times with EtOAc
  4. washThe combined organic layers are washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue is dissolved in anhydrous THF (25 ml)
  9. temperaturerefluxed for 1 hour
  10. temperatureAfter cooling
  11. filtrationThe precipitate is filtered off
  12. concentrationthe filtrate is concentrated in vacuo
  13. customThe residue is purified via flash chromatography (EtOAc I MeOH 95:5)

Sources & evidence

ORD record
ord-c5de8b801f26448a8deb388a3875dac1
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Reaction notes

Loading…