Chloromethyl Methyl Ether → 2-chloro-5-(MethoxyMethoxy)pyridine

HRID 1640899Notes

Reaction equation

HRID 1640899 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.Cl[CH2:12][O:13][CH3:14]>CN(C=O)C.C(OCC)(=O)C.O.[Cl-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][O:13][CH3:14])=[CH:6][N:5]=1

Participants

8

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 24758Sodium hydrideHCID 8198212-Chloro-5-hydroxypyridine

Product 1

HCID 587641932-chloro-5-(MethoxyMethoxy)pyridineYield 81%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 5234Sodium ChlorideSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Suspend sodium hydride (3.7 g, 93 mmol) in DMF (50 mL) and add a solution of 2-chloro-5-hydroxypyridine (10 g, 77 mmol) in DMF (20 mL) dropwise over 45 min. Stir the resulting solution at RT for 1.5 h. Add chloromethylmethyl ether (6.6 mL, 86 mmol) dropwise over 45 min. Stir the resulting mixture at RT for 12 h. Dilute the mixture with ethyl acetate, water, and saturated aqueous sodium chloride. Isolate the organic solution and wash with three portions of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30% ethyl acetate in hexane over 20 min and then hold at 30% ethyl acetate in hexane for 30 min to give the title compound 10.8 g (81%) as a clear oil. MS (ES) m/z 174.0 [M+1]+.

Workup

  1. stirringStir the resulting mixture at RT for 12 h
  2. customIsolate the organic solution
  3. washwash with three portions of water, one portion of saturated aqueous sodium chloride
  4. dry with materialdry over sodium sulfate
  5. filtrationfilter
  6. concentrationconcentrate in vacuo
  7. customPurify the crude product by column chromatography on 330 g of silica gel eluting with a gradient from hexane to 30% ethyl acetate in hexane over 20 min
  8. waithold at 30% ethyl acetate in hexane for 30 min

Sources & evidence

ORD record
ord-ebac8bc3254c4a16ba8538215c7b9902
Source dataset
uspto-grants-2012_02
Patent number
US08114872B2

Reaction notes

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