Chloromethyl Methyl Ether → 2-Methoxy-5-(methoxymethoxy)pyridine

HRID 1471707Notes

Reaction equation

HRID 1471707 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][O:13][CH3:14])=[CH:7][N:8]=1

Participants

5

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 24758Sodium hydrideHCID 116223355-Hydroxy-2-methoxypyridine

Product 1

HCID 120277842-Methoxy-5-(methoxymethoxy)pyridineYield 89.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
2.5 °C

Procedure

To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol, 1 eq.) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol, 1.5 eq.) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min, added chloromethyl methyl ether (15.5 g, 0.19 mol, 1.2 eq.), stirred at 0-5° C. for another 20 min, and quenched with NH4Cl(sat.) solution. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified on silica gel using 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. 1H NMR (400 MHz; CDCl3) 7.97 (d, 1H), 7.35 (dd, 1H), 6.70 (d, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.51 (s, 3H). LRMS (M+H+) m/z 170.1

Workup

  1. additionUpon the completion of addition
  2. stirringstirred at 0-5° C. for another 20 min
  3. customquenched with NH4Cl(sat.) solution
  4. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  5. washthe combined organic layers were washed with water and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. custompurified on silica gel using 25% EtOAc/hexanes as eluent

Sources & evidence

ORD record
ord-a10aa9be3c524ad2a7407cb46a48c3f4
Source dataset
uspto-grants-2015_04
Patent number
US09012450B2

Reaction notes

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