2,2,2-Trifluoro-1-methoxyethanol → 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one

HRID 913026

Reaction equation

HRID 913026 reaction equation
[F:1][CH:2]([F:12])[C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[C:13]([CH:17](OC)[OH:18])([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>>[F:12][CH:2]([F:1])[C:3]1[N:4]([CH3:11])[C:5]([CH:17]([OH:18])[C:13]([F:16])([F:15])[F:14])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1

Participants

4

Reactant 3

HCID 98922,2,2-Trifluoro-1-methoxyethanolHCID 11430Potassium CarbonateHCID 250189082-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one

Product 1

HCID 250186556-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-oneYield 4.5%

Conditions

Temperature
100 °C

Procedure

A suspension of 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one (0.50 g, 2.85 mmol), CF3CH(OH)OCH3 (2.37 g, 18.2 mmol) and potassium carbonate (0.122 g, 0.88 mmol) in a sealed parallel reactor test tube was heated to about 100° C. The progress of the reaction was monitored by HPLC Method 1 (Example 24), and only one major product peak was detected (HPLC peak percent area was about 20% after 1.5 h, and 38% after 3 h). The reaction mixture was heated for another 21 h, then cooled down to RT, and some white solid separated. The solid was collected by suction filtration. HPLC analysis of the solid dissolved in methanol showed the presence of 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one and 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one in 18/82 ratio. A portion of the solid was purified by column chromatography on silica gel (conc. NH4OH/isopropanol 10/100 v/v as eluant) to afford 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (35 mg). HPLC Method 1 (Example 24), RT=11.3 min, HPLC purity (peak percent area): 97.9% at λ=280 nm. 1H NMR (DMSO-d6+1 drop of D2O) δ ppm: 7.12 (t, J=52.8 Hz, 1H), 6.56 (s, 1H), 5.83 (b, 1H), 3.79 (s, 3H). 19F NMR (DMSO-d6+1 drop of D2O) δ ppm: −73.3 (3F), −117.8 (2F). MS-ESI (m/z) 274.1 [M+1]+, 256.1, 228.1, 208.1 (100%), 180.1.

Workup

  1. custom(HPLC peak percent area was about 20% after 1.5 h, and 38% after 3 h)
  2. temperatureThe reaction mixture was heated for another 21 h
  3. temperaturecooled down to RT
  4. customsome white solid separated
  5. filtrationThe solid was collected by suction filtration
  6. dissolutionHPLC analysis of the solid dissolved in methanol
  7. customA portion of the solid was purified by column chromatography on silica gel (conc. NH4OH/isopropanol 10/100 v/v as eluant)

Sources & evidence

ORD record
ord-b5d419c31068426ba1d2d8bfd7a3f0f1
Source dataset
uspto-grants-2011_09
Patent number
US08026261B2

Linked notes

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