Methanol → Methyl 2-(hydroxymethyl)pyridine-4-carboxylate

HRID 1963241Notes

Reaction equation

HRID 1963241 reaction equation
[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:28][OH:29]>O>[OH:29][CH2:28][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]([O:9][CH3:10])=[O:8]

Participants

6

Reactant 4

HCID 887MethanolHCID 1118Sulfuric AcidHCID 62648Ammonium PersulfateHCID 227085Methyl isonicotinate

Product 1

HCID 13276248Methyl 2-(hydroxymethyl)pyridine-4-carboxylateYield 32%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

The reaction was performed in 2 separate 1000 mL round-bottomed flasks. To a solution of methyl isonicotinate (70 g, 510.44 mmol) and sulfuric acid (2.340 mL, 43.90 mmol) in MeOH (700 mL) under reflux, was added a solution of ammonium peroxydisulfate (210 g, 918.80 mmol) in water (350 mL) over 20 min. The reaction was refluxed for 20 min and was then allowed to cool to room temperature. The solid was filtered off and washed with MeOH. MeOH was removed from the filtrate under reduced pressure and then was neutralised by cautious stepwise addition of solid Na2CO3 under ice-cooling. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The dark-brown residue was treated with cyclohexane (3×300 mL) and the cyclohexane phase was decanted. The remaining dark-brown residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns. A gradient from 25% to 100% of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(hydroxymethyl)isonicotinate (27.5 g, 32%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.90 (s, 3H), 4.78 (s, 2H), 7.57-7.90 (m, 2H), 8.64 (s, 1H). MS m/z 168 (M+H)+

Workup

  1. customseparate 1000 mL round-bottomed flasks
  2. temperatureThe reaction was refluxed for 20 min
  3. filtrationThe solid was filtered off
  4. washwashed with MeOH
  5. customMeOH was removed from the filtrate under reduced pressure
  6. additionwas neutralised by cautious stepwise addition of solid Na2CO3 under ice-
  7. temperaturecooling
  8. extractionThe aqueous solution was extracted with ethyl acetate
  9. dry with materialthe combined organic layers were dried with Na2SO4
  10. customevaporated
  11. additionThe dark-brown residue was treated with cyclohexane (3×300 mL)
  12. customthe cyclohexane phase was decanted
  13. customThe remaining dark-brown residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns

Sources & evidence

ORD record
ord-b764f90b9b744eb7bd070d3b026f22d8
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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