Hydrochloric Acid → 2-{5-Fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile

HRID 253283Notes

Reaction equation

HRID 253283 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Na+].[C:23](C1NC=CN=1)(=[O:25])[CH3:24].Cl>C1COCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([C:23](=[O:25])[CH3:24])[C:9]#[N:10])[CH:7]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 5389722-AcetylimidazoleHCID 66891788HCID 66891788, compound

Product 1

HCID 668904882-{5-Fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrileYield 80%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

A solution of {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol) in THF (60 mL) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.64 g, 41 mmol) was added followed by acetylimidazole (3.2 g, 29.3 mmol). The mixture was heated to 40° C. for 15 min before cooling to rt. Water was added, and this mixture was acidified with 1 N HCl (45 mL). Ethyl acetate was added and the layers were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile as a colorless oil (4.9 g, 15.6 mmol, 80% yield). 1H NMR (400 MHz, CDCl3): (mixture of tautomers) δ 9.70 (s, 0.2H), 7.42-7.33 (m, 5H), 6.82 (dd, 0.2H), 6.75 (dd, 0.8H) 6.69-6.64 (m, 1H), 5.09 (s, 2H), 4.90 (s, 0.8H), 3.89 (s, 2.1H), 3.83 (s, 0.9H), 2.38 (s, 0.9H), 2.29 (s, 2.11H).

Workup

  1. temperaturebefore cooling to rt
  2. customthe layers were partitioned
  3. extractionThe aqueous phase was extracted with ethyl acetate
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate)

Sources & evidence

ORD record
ord-1a803b3b730d4c2db5b844eba21d18d9
Source dataset
uspto-grants-2011_01
Patent number
US07872014B2

Reaction notes

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