Triethylamine → 5-Chloro-3-(3,5-difluorophenyl)isoxazole

HRID 1264530Notes

Reaction equation

HRID 1264530 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:5]([CH2:7][C:8](OCC)=[O:9])=O.[ClH:17].[NH2:18]O.C(N(CC)CC)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]=[C:8]([Cl:17])[O:9][N:18]=2)[CH:13]=[C:14]([F:16])[CH:15]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 443297Hydroxyamine hydrochlorideHCID 13550003Ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate

Product 1

HCID 186126645-Chloro-3-(3,5-difluorophenyl)isoxazoleYield 35%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A mixture of ethyl 3,5-difluorobenzoylacetate (1.87 g, 8.19 mmol) and hydroxylamine hydrochloride (626 mg, 9.01 mmol) in acetic acid (24 ml) is stirred at reflux for 1 hr. The crude reaction mixture is concentrated in vacuo and azeotroped with toluene twice. The crude material is suspended in phosphorus oxychloride (37 ml) and triethyl amine (2.37 ml, 17.1 mmol) is added slowly. The reaction mixture is stirred at reflux for 2 days, concentrated in vacuo and azeothroped with toluene 3 times. The residue is dissolved in dichloromethane and passed on a plug of silica gel (elution with dichloromethane. After concentration in vacuo, the crude material is purified by flash chromatography (silica gel, dry loading, 5% diethyl ether in hexane) to give 3-(3,5-difluorophenyl)-5-chloroisoxazole (600 mg, 35%) as an off-white solid.

Workup

  1. temperatureat reflux for 1 hr
  2. customThe crude reaction mixture
  3. concentrationis concentrated in vacuo
  4. customazeotroped with toluene twice
  5. stirringThe reaction mixture is stirred
  6. temperatureat reflux for 2 days
  7. concentrationconcentrated in vacuo and azeothroped with toluene 3 times
  8. dissolutionThe residue is dissolved in dichloromethane
  9. washelution with dichloromethane
  10. concentrationAfter concentration in vacuo
  11. customthe crude material is purified by flash chromatography (silica gel, dry loading, 5% diethyl ether in hexane)

Sources & evidence

ORD record
ord-990ef87052cc4b5ba17e16574745f767
Source dataset
uspto-grants-2003_04
Patent number
US06544982B1

Reaction notes

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