Acetamidomalonic acid diethyl ester → Diethyl 2-acetamido-2-(5-nitropyridin-2-yl)propanedioate

HRID 2203338Notes

Reaction equation

HRID 2203338 reaction equation
[H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C)C=O.Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]

Participants

6

Reactant 3

HCID 14041Acetamidomalonic acid diethyl esterHCID 24758Sodium hydrideHCID 783082-Chloro-5-nitropyridine2×

Product 1

HCID 321593Diethyl 2-acetamido-2-(5-nitropyridin-2-yl)propanedioate

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
45 °C

Procedure

To a stirred slurry of sodium hydride (46 g, 1 mol, 50% oil dispersion) in dimethylformamide (500 mL, distilled from calcium oxide) was slowly added a solution of diethyl acetamidomalonate (217 g, 1 mol) in dimethylformamide (1200 mL). After the initial reaction, the slurry was heated to 45° C. for 1.5 hours and then 2-chloro-5-nitropyridine (159 g, 1 mol) in DMF (800 mL) was added. The mixture became dark brown during addition of the 2-chloro-5-nitropyridine. The mixture was stirred at 45° C. overnight. After cooling, the mixture was diluted with 1000 mL hydrochloric acid (0.2 N), and then extracted with dichloromethane (3×1200 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to give a dark brown oil. The oil was dry-loaded on silica gel and chromatographed on a dry-packed silica gel column. The column was eluted with petroleum ether-ethyl acetate (8:1 and then 5:1). Fractions containing the indicated compound were combined and concentrated to give pale yellow solid. Mp 82-83° C.

Workup

  1. customAfter the initial reaction
  2. temperatureAfter cooling
  3. extractionextracted with dichloromethane (3×1200 mL)
  4. dry with materialThe combined organic phases were dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. customthe solvent evaporated
  7. customto give a dark brown oil
  8. customchromatographed on a dry-packed silica gel column
  9. washThe column was eluted with petroleum ether-ethyl acetate (8:1
  10. additionFractions containing the indicated compound
  11. concentrationconcentrated
  12. customto give pale yellow solid

Sources & evidence

ORD record
ord-8bc007f2c12347898f7a131ae0b4356a
Source dataset
uspto-grants-2016_06
Patent number
US09365574B2

Reaction notes

Loading…