Methyl iodide → Methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate

HRID 521927Notes

Reaction equation

HRID 521927 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].F[C:24]1C=C(C(O)C)C=C(F)C=1C1N=C(C(O)=O)C=CC=1F.[H-].[Na+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:24])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 867138656-(2,6-Difluoro-4-(1-hydroxyethyl)phenyl)-5-fluoropicolinic acidHCID 86713868Methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate

Product 1

HCID 86713867Methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinateYield 63%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 2 days
  2. customThe reaction mixture was quenched with water
  3. extractionextracted with EtOAc
  4. washThe organic layer was washed with brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe residue was purified on silica
  8. washeluted with 0 to 50% EtOAc in Heptane

Sources & evidence

ORD record
ord-53dbc73a878c4dc68b3af3c2036d35ff
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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