Thionyl Chloride → Ethyl 3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate

HRID 2388177Notes

Reaction equation

HRID 2388177 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]2[C:14]3[CH:13]=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:19]([OH:20])[C:18]=3[O:17][N:16]=2)=[CH:25][CH:26]=1

Participants

6

Reactant 3

HCID 24386Thionyl ChlorideHCID 23665647Potassium tert-butoxideHCID 67530684Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-fluorophenyl)isoxazole-5-carboxylate

Product 1

HCID 67530129Ethyl 3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylateYield 69%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-fluorophenyl)isoxazole-5-carboxylate (8.7 g, 17.4 mmol) was dissolved in 150 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (34.8 mL, 34.8 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 30 mL of 1M HCl and 200 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 7.54 g of crude oil. The crude intermediate was dissolved in 100 mL of CH2Cl2. Thionyl chloride (1.8 mL, 24.9 mmol) was added and within minutes a precipitate began to form. The reaction mixture was stirred for another hour and the mixture was filtered through a medium porosity funnel. The solid was rinsed twice with cold CH2Cl2 and dried under vacuum to give 3.63 g of the title compound. MS: (+) m/z 303.37 (M+1).

Workup

  1. customto evaporate spontaneously
  2. customThe reaction mixture was quenched with 30 mL of 1M HCl and 200 mL of saturated ammonium chloride solution
  3. extractionThe product was extracted with EtOAc
  4. dry with materialthe organic layer was dried over MgSO4
  5. concentrationconcentrated
  6. customto give 7.54 g of crude oil
  7. customto form
  8. stirringThe reaction mixture was stirred for another hour
  9. filtrationthe mixture was filtered through a medium porosity funnel
  10. washThe solid was rinsed twice with cold CH2Cl2
  11. customdried under vacuum

Sources & evidence

ORD record
ord-7a32cf3e377e48abb496301013a71a14
Source dataset
uspto-grants-2012_09
Patent number
US08269008B2

Reaction notes

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