Ethyl bromoacetate → [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl ester

HRID 11323Notes

Reaction equation

HRID 11323 reaction equation
[H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])=[CH:8][CH:9]=1)[CH3:26]

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 133747555-(4-Hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

Product 1

HCID 15682655[4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl esterYield 29%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.16 g, 29.0 mmol) in N,N-dimethylformamide (50 mL), was added at 0° C. a solution of 5-(4-hydroxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (6, 3.25 g, 14.4 mmol) in N,N-dimethylformamide (50 mL). The mixture was stirred at ambient temperature for 30 min. A solution of ethyl 2-bromoacetate (2.0 mL, 18.0 mmol) in N,N-dimethylformamide (10 mL) was added at 0° C., the mixture was stirred for 30 min at 0° C., for 30 min at ambient temperature and then for 45 min at 80° C. The mixture was allowed to cool to room temperature, concentrated in vacuo and re-dissolved in ethyl acetate (300 mL). The solution was extracted with water (3×150 mL). The combined aqueous layers were acidified to pH 2 with aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (50 g) using 2% methanol in dichloromethane as eluent to give [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl ester (7) as light yellow powder (1.3 g, 29% yield, 80–90% pure by LC-MS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.70 (d, 1H); 7.19 (m, 2H); 6.72 (m, 2H); 4.90 (s, 2H); 4.12 (q, 2H); 1.71 (s, 3H); 1.30 (t, 3H).

Workup

  1. stirringthe mixture was stirred for 30 min at 0° C., for 30 min at ambient temperature
  2. waitfor 45 min at 80° C
  3. temperatureto cool to room temperature
  4. concentrationconcentrated in vacuo
  5. dissolutionre-dissolved in ethyl acetate (300 mL)
  6. extractionThe solution was extracted with water (3×150 mL)
  7. extractionextracted with ethyl acetate (3×150 mL)
  8. dry with materialThe combined organic layers were dried (MgSO4)
  9. customevaporated to dryness
  10. customThe residue was purified by column chromatography on silica gel (50 g)

Sources & evidence

ORD record
ord-6d859fe22634473586ac9c6a9326aa48
Source dataset
uspto-grants-2006_08
Patent number
US07098211B2

Reaction notes

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