Sodium Hydroxide → 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid

HRID 1911658Notes

Reaction equation

HRID 1911658 reaction equation
C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 665992926-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester

Product 1

HCID 665992136-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidYield 45%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (191 mg, 42%) as a white solid. To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (3.89 g, 120 mmol) in ethanol (40 mL) was added aqueous sodium hydroxide (1 M, 36.0 mL, 36.0 mmol). After heating at reflux for 2 h it was cooled to ambient temperature and concentrated. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by washing with tert-butylmethylether (100 mL). The aqueous phase was acidified with aqueous hydrogen chloride (conc.) to pH=1 and extracted with tert-butylmethylether (100 mL). The organic layer was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL). Drying over sodium sulfate and concentration afforded the title compound (1.68 g, 45%) as an off white solid. MS: m/e=309.3 [M−H]−.

Workup

  1. temperatureAfter heating
  2. temperatureat reflux for 2 h it
  3. concentrationconcentrated
  4. additionAddition of aqueous sodium hydroxide (1 M, 50 mL)
  5. washby washing with tert-butylmethylether (100 mL)
  6. extractionextracted with tert-butylmethylether (100 mL)
  7. washThe organic layer was washed with water (50 mL) and aqueous sodium chloride (saturated, 50 mL)
  8. dry with materialDrying over sodium sulfate and concentration

Sources & evidence

ORD record
ord-bf7a6e1c020346a7a9e246d7891b8629
Source dataset
uspto-grants-2013_12
Patent number
US08604062B2

Reaction notes

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