Acrylic Acid → N-(3-Fluorophenyl)-beta-alanine

HRID 1515326Notes

Reaction equation

HRID 1515326 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1

Participants

4

Reactant 2

HCID 6581Acrylic AcidHCID 97423-Fluoroaniline

Product 1

HCID 17244968N-(3-Fluorophenyl)-beta-alanineYield 51%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To 3-fluoroaniline (5.0 g), water (50 ml) and acrylic acid (3.6 g) were added and heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was stirred for 3 days and further heated under reflux for 7 hours. After cooling at room temperature, the solvent was distilled off under reduced pressure. To the resulting residue, 8M aqueous sodium hydroxide and chloroform were added to separate the aqueous layer. The separated aqueous layer was adjusted to pH 3 with 12M aqueous hydrochloric acid under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1) to give 3-[N-(3-fluorophenyl)]aminopropionic acid (4.2 g) as a light-yellow powder. The compound thus obtained (3.8 g) was added to polyphosphoric acid (35g) heated at 130° C., followed by stirring for 1.5 hours. The reaction mixture was neutralized by addition of water and 8M aqueous sodium hydroxide under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 4:1 to 2:1) to give the titled compound of low polarity, i.e., 7-fluoro-2,3-dihydro-1H-quinolin-4-one (810 mg) as a yellow powder. On the other hand, a yellow oil obtained as a compound of high polarity was crystallized from a mixture of n-hexane and diethyl ether to give the other titled compound, i.e., 5-fluoro-2,3-dihydro-1H-quinolin-4-one (110 mg) as a yellow powder.

Workup

  1. temperatureheated
  2. temperatureunder reflux for 3 hours
  3. temperaturefurther heated
  4. temperatureunder reflux for 7 hours
  5. temperatureAfter cooling at room temperature
  6. distillationthe solvent was distilled off under reduced pressure
  7. additionTo the resulting residue, 8M aqueous sodium hydroxide and chloroform were added
  8. customto separate the aqueous layer
  9. extractionextracted with chloroform
  10. dry with materialThe extracted organic layer was dried over anhydrous magnesium sulfate
  11. filtrationfiltered
  12. customto remove the desiccant
  13. distillationby distilling off the solvent under reduced pressure
  14. customThe resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1)

Sources & evidence

ORD record
ord-0dbd5f4825364a31922df504d5d0659a
Source dataset
uspto-grants-2012_07
Patent number
US08222417B2

Reaction notes

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