Acetic Acid → 3-Ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine

HRID 1921361Notes

Reaction equation

HRID 1921361 reaction equation
C[N:2]([CH:4]=[N:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.Cl.NO.[OH-].[Na+].C(O)(=O)C>O1CCOCC1.O>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[O:18][N:2]=[CH:4][N:5]=2)[CH:12]=1)[CH3:14]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 443297Hydroxyamine hydrochlorideHCID 67492560N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide

Product 1

HCID 674923793-Ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridineYield 56%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

In a round bottom flask under a nitrogen atmosphere a mixture of N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 1.13 mmol scale) of Step 2, Example 16, hydroxylamine hydrochloride (103 mg, 1.48 mmol) and sodium hydroxide (59.4 mg, 1.48 mmol) and glacial acetic acid (1.7 mL) is treated with water (0.85 mL) and 1,4-dioxane (1.24 mL). The resulting dark mixture is stirred at 90° C. for 45 min. The reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The mixture is treated with excess solid sodium bicarbonate, the dichloromethane layer is separated and the aqueous layer is extracted with 2 further portions of dichloromethane. The combined organic layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine as a white solid (138 mg, 56% yield, 2 steps). NMR (CDCl3, δ ppm): 8.45 (1H, s), 8.05 (1H, s), 4.02 (3H, s), 2.82 (3H, s), 2.62 (2H, q), 1.23 (3H, t).

Workup

  1. customThe reaction mixture is evaporated
  2. customthe residue is partitioned between water and dichloromethane
  3. additionThe mixture is treated with excess solid sodium bicarbonate
  4. customthe dichloromethane layer is separated
  5. extractionthe aqueous layer is extracted with 2 further portions of dichloromethane
  6. dry with materialThe combined organic layer is dried over magnesium sulfate
  7. customevaporated
  8. customThe crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane
  9. additionFractions containing the product
  10. customevaporated
  11. customre-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane
  12. additionFractions containing the product
  13. customthe solvent evaporated

Sources & evidence

ORD record
ord-3c94c952562e4c8bbb6f05e0784ae7c8
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

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