Sodium hydride → 6-[3-(3,4-Difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester

HRID 1514706Notes

Reaction equation

HRID 1514706 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:15]([CH2:16][OH:17])=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=1.[Cl-].[NH4+]>C1COCC1.O>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([O:17][CH2:16][C:15]2[C:11]([C:6]3[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=3)=[N:12][O:13][C:14]=2/[CH:18]=[CH:19]/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:28][CH:29]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 254249Methyl 6-chloropyridine-3-carboxylateHCID 66718189[3-(3,4-Difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-yl]-methanol

Product 1

HCID 667182936-[3-(3,4-Difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl esterYield 81%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

To a suspension of sodium hydride (1.23 mg, 28.1 mmol) in 45 mL THF was added a solution of [3-(3,4-difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-yl]-methanol (8.0 g, 25.5 mmol) in THF (84 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. A solution of methyl 6-chloronicotinate (4.92 g, 28.1 mmol) in THF (84 mL) was added. The reaction was stirred at room temperature for 3 h and water (150 mL) and saturated aqueous ammonium chloride solution (100 mL) were added. Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 2:3) afforded the title compound (9.24 g, 81%) as a yellow solid. MS: m/e=507.1 [M+CH3COO]−.

Workup

  1. stirringThe reaction was stirred at room temperature for 3 h
  2. extractionExtraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 2:3)

Sources & evidence

ORD record
ord-fb679c45dd86495d87dea4b177fafc2d
Source dataset
uspto-grants-2012_07
Patent number
US08222246B2

Reaction notes

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