Tert-butyl 2-cyano-2-(5-methoxypyridin-2-yl)acetate → 2-(5-Methoxypyridin-2-yl)acetic acid

HRID 1913411Notes

Reaction equation

HRID 1913411 reaction equation
C([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=1)[C:4]([O:6]C(C)(C)C)=[O:5])#N>O.Cl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:3][C:4]([OH:6])=[O:5])=[N:12][CH:13]=1

Participants

4

Reactant 1

HCID 67409891Tert-butyl 2-cyano-2-(5-methoxypyridin-2-yl)acetate

Product 1

HCID 584384902-(5-Methoxypyridin-2-yl)acetic acidYield 53.7%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

The crude tert-butyl cyano(5-methoxypyridin-2-yl)acetate (3.46 g) was suspended in a mixture of 45 mL of water and 45 mL of concentrated HCl. The mixture was heated at 60° C. for 1 hour and at reflux overnight. The reaction was cooled and the water was removed under vacuum. The oily solid residue was redissolved in a minimal amount of water (˜50-70 mL) and 2N NaOH was added to adjust the pH to approximately 14. The solution was washed with diethyl ether and was reacidified to pH 4 with 2N HCl and concentrated to dryness to give a white solid. This solid was triturated in hot THF (3×) and the combined supernatants were cooled in an icebath to initiate crystallization. After 20 minutes, the solid was collected by filtration washing with heptanes to give (5-methoxypyridin-2-yl)acetic acid (1.25 g). A second crop of product precipitated from the filtrate (0.39 g). The filtrate was concentrated, and the material was triturated with hot ethyl acetate and heptanes to provide a third crop of product as a brown solid (0.11 g of lower purity). The total yield of SM-1aa was 1.75 g (98%). MS (ES+) 168.1 (M+H)+. 1H NMR (DMSO-d6) δ 3.66 (s, 2H), 3.81 (s, 3H), 7.27 (d, 1H), 7.33-7.36 (m, 1H), 8.18 (d, 1H).

Workup

  1. temperatureat reflux overnight
  2. temperatureThe reaction was cooled
  3. customthe water was removed under vacuum
  4. dissolutionThe oily solid residue was redissolved in a minimal amount of water (˜50-70 mL) and 2N NaOH
  5. additionwas added
  6. washThe solution was washed with diethyl ether
  7. concentrationconcentrated to dryness
  8. customto give a white solid
  9. customThis solid was triturated in hot THF (3×)
  10. temperaturethe combined supernatants were cooled in an icebath
  11. customcrystallization
  12. filtrationthe solid was collected by filtration
  13. washwashing with heptanes

Sources & evidence

ORD record
ord-946ed2646e10468d927d46d223dbbc03
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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