Sodium hydride → 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester

HRID 1911657Notes

Reaction equation

HRID 1911657 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:20]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 254249Methyl 6-chloropyridine-3-carboxylateHCID 2776149(5-Methyl-3-phenyl-1,2-oxazol-4-yl)methanol

Product 1

HCID 665992926-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl esterYield 55.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

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. additionwas added
  2. washwashed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL)
  3. extractionThe combined aqueous layers were extracted with ethyl acetate (10 mL)
  4. dry with materialAfter drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30)

Sources & evidence

ORD record
ord-328457f50680441cb07b7c6c4cf2663e
Source dataset
uspto-grants-2013_12
Patent number
US08604062B2

Reaction notes

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