2-Fluoro-3-(methoxymethoxy)pyridine → (2-Fluoro-3-(methoxymethoxy)pyridin-4-yl)(2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol

HRID 335950Notes

Reaction equation

HRID 335950 reaction equation
C([Li])CCC.[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1.[F:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][C:19]=1[CH:20]=[O:21]>C1COCC1>[F:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([CH:20]([C:19]2[CH:22]=[C:23]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:18]=2[F:17])[OH:21])[CH:10]=[CH:9][N:8]=1

Participants

5

Reactant 3

HCID 673829612-Fluoro-3-(methoxymethoxy)pyridineHCID 866584942-Fluoro-5-(2-fluoropyridin-3-yl)benzaldehydeHCID 178418339Butyllithium

Product 1

HCID 67383057(2-Fluoro-3-(methoxymethoxy)pyridin-4-yl)(2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanolYield 68.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

DIPA (3.5 mL, 24.97 mmol) was dissolved in dry THF (10 mL) under nitrogen and cooled in a dry ice bath. Butyllithium solution (2.5 m in hexanes, 10.0 mL, 25.00 mmol) was added and after stirring for a few minutes 2-fluoro-3-(methoxymethoxy)pyridine (3.71 g, 23.64 mmol) in dry THF (25 mL) was added dropwise. The reaction was stirred for 1 h. A solution of 2-fluoro-5-(2-fluoropyridin-3-yl)benzaldehyde (4.71 g, 21.49 mmol) in dry THF (40 mL) was added dropwise over 10 min. The reaction was removed from the cold bath and stirred for an additional 15 min. Saturated sodium bicarbonate (20 mL) was added followed by EtOAc (300 mL) and water (400 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (2-fluoro-3-(methoxymethoxy)pyridin-4-yl)(2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (5.52 g, 14.67 mmol). MS m/z=377.1 [M+H]+. Calculated for C19H15F3N2O3: 376.10.

Workup

  1. temperaturecooled in a dry ice bath
  2. additionwas added dropwise
  3. customThe reaction was removed from the cold bath
  4. stirringstirred for an additional 15 min
  5. additionSaturated sodium bicarbonate (20 mL) was added
  6. additionThe phases were mixed
  7. customseparated
  8. dry with materialthe organic dried with magnesium sulfate
  9. custombefore evaporating to dryness under reduced pressure
  10. customPurification

Sources & evidence

ORD record
ord-8353aa960090478498bd3d31c871439f
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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