Chloromethyl Methyl Ether → 4-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine

HRID 335954Notes

Reaction equation

HRID 335954 reaction equation
[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[OH-].[Na+].[Br:17]Br.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][O:32][CH2:33]Cl>CC(O)=O.CCOC(C)=O.O>[Br:17][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([F:1])[C:7]=1[O:8][CH2:31][O:32][CH3:33]

Participants

10

Reactant 6

HCID 7864Chloromethyl Methyl EtherHCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 24408BromineHCID 24437Sodium SulfiteHCID 673830042-fluoro-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol

Product 1

HCID 673828784-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridineYield 58.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Fluoro-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol (1.90 g, 9.63 mmol) was dissolved in mixture of HOAc (100 mL) and NaOH (1.0 N, 20 mL, 20.00 mmol). The mixture was cooled in an ice bath and bromine (0.6 mL, 11.65 mmol) was added. It was stirred for 15 min. Sodium sulfite (1.1 g) was added and the mixture stirred for 5 min. Water (300 mL) and EtOAc (400 mL) were added and the phases mixed and separated. The organic was dried with brine (200 mL) then magnesium sulfate before evaporating to dryness under reduced pressure and further dried under high vacuo. The crude was dissolved in ACN (100 mL) and treated with cesium carbonate (0.98 mL, 12.28 mmol). It was cooled in an ice bath and chloromethyl methyl ether (0.90 mL, 11.85 mmol) was added slowly over 2 min. The reaction was stirred for 90 minutes. The mixture was evaporated to dryness under reduced pressure and the crude partitioned between water (300 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 4-bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (1.80 g, 5.62 mmol, 58.4% yield) as a pale yellow oil. MS m/z=320.0, 322.0 [M+H]+. Calculated for C12H15BrFNO3: 319.02.

Workup

  1. temperatureThe mixture was cooled in an ice bath
  2. stirringthe mixture stirred for 5 min
  3. additionthe phases mixed
  4. customseparated
  5. dry with materialThe organic was dried with brine (200 mL)
  6. custommagnesium sulfate before evaporating to dryness under reduced pressure
  7. customfurther dried under high vacuo
  8. dissolutionThe crude was dissolved in ACN (100 mL)
  9. temperatureIt was cooled in an ice bath
  10. stirringThe reaction was stirred for 90 minutes
  11. customThe mixture was evaporated to dryness under reduced pressure
  12. customthe crude partitioned between water (300 mL) and ethyl acetate (300 mL)
  13. dry with materialThe organic was dried with magnesium sulfate
  14. customevaporated to dryness under reduced pressure
  15. customPurification

Sources & evidence

ORD record
ord-c86f1fdeef664b9b9675a6c7ad7d0ff5
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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