Hydrochloric Acid → 2-Fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine

HRID 455697Notes

Reaction equation

HRID 455697 reaction equation
Br[C:2]1[C:3]([F:14])=[N:4][C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:7]=1.C([Li])CCC.B([O:29][CH:30](C)C)(OC(C)C)OC(C)C.[OH-].[Na+].OO.Cl.[C:38]([O-])([O-])=[O:39].[K+].[K+].COCCl>C1COCC1.[Cl-].[Na+].O.C(OCC)C>[F:14][C:3]1[C:2]([O:39][CH2:38][O:29][CH3:30])=[CH:7][CH:6]=[C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1

Participants

12

Reactant 8

HCID 313Hydrochloric AcidHCID 784Hydrogen PeroxideHCID 7864Chloromethyl Methyl Ether2×HCID 11430Potassium Carbonate2×HCID 14798Sodium HydroxideHCID 21531Triisopropyl borateHCID 574756593-Bromo-2-fluoro-6-(neopentyloxy)pyridineHCID 178418339Butyllithium

Product 1

HCID 574756602-Fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridineYield 55.4%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-100 °C

Procedure

A solution of 3-bromo-2-fluoro-6-(neopentyloxy)pyridine (5.6 g, 21.36 mmol) in THF (50 mL) was cooled to −100° C. and a solution of n-butyllithium (1.6M in hexane; 14.69 mL, 23.50 mmol) was added drop wise. The reaction mixture was allowed to stir for 10 min at −100° C. Triisopropyl borate (7.35 mL, 32.0 mmol) was added and the reaction mixture was allowed to warm to rt. Aqueous NaOH solution (5M; 29.9 mL, 150 mmol) was added, followed by hydrogen peroxide (30%; 15.28 mL, 150 mmol). The reaction mixture was allowed to stir for 30 min at rt. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure, the residue was dissolved in acetone (50 mL) and the solution was cooled to 0° C. K2CO3 (3.25 g, 23.50 mmol) was added, followed by chloromethyl methyl ether (1.785 mL, 23.50 mmol). After 30 min, additional K2CO3 (3.25 g, 23.50 mmol) and chloromethyl methyl ether (1.785 mL, 23.50 mmol) were added and the reaction mixture was warmed to rt. After 2 h brine and diethyl ether were added. The organic was separated and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc/hexanes) to yield 2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.88 g, 11.84 mmol).

Workup

  1. temperatureto warm to rt
  2. stirringto stir for 30 min at rt
  3. extractionextracted with EtOAc
  4. customThe organic phase was separated
  5. dry with materialdried over MgSO4
  6. customThe solvent was removed under reduced pressure
  7. dissolutionthe residue was dissolved in acetone (50 mL)
  8. temperaturethe solution was cooled to 0° C
  9. waitAfter 30 min
  10. temperaturethe reaction mixture was warmed to rt
  11. customThe organic was separated
  12. dry with materialdried over magnesium sulfate
  13. customThe solvent was removed under reduced pressure
  14. customThe residue was purified by flash chromatography (0-20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-f3a6bc3d4f9740d9aa4c7601ae72e136
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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