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

HRID 44060Notes

Reaction equation

HRID 44060 reaction equation
[H-].[Na+].[CH2:3]([O:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18](Cl)[O:19][CH3:20]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:15][N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 24758Sodium hydrideHCID 425530416-(Benzyloxy)pyridin-3-ol

Product 1

HCID 672176842-(Benzyloxy)-5-(methoxymethoxy)pyridineYield 89%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (1.2 g, 29.8 mmol) was added to a stirring solution of 6-(benzyloxy)pyridin-3-ol (5.0 g, 24.85 mmol) in DMF (100 mL) at 0° C. Then it was allowed to warm to room temperature and stir for 25 min then was treated with MOM-Cl (2.55 mL, 28.6 mmol) and the reaction was allowed to stir for 2 hrs. The mixture was quenched with H2O then concentrated about 80% then diluted with EtOAc and washed with H2O, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(benzyloxy)-5-(methoxymethoxy)pyridine (5.41 g, 22.1 mmol, 89% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97 (1H, d, J=3.01 Hz), 7.42-7.49 (2H, m), 7.29-7.41 (4H, m), 6.76 (1H, d, J=9.03 Hz), 5.34 (2H, s), 5.12 (2H, s), 3.50 (3H, s). LC-MS retention time: 1.88 min; m/z (MH+): 246. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Workup

  1. stirringto stir for 2 hrs
  2. customThe mixture was quenched with H2O
  3. concentrationthen concentrated about 80%
  4. additionthen diluted with EtOAc
  5. washwashed with H2O
  6. dry with materialThe organic phase was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customwas purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm)

Sources & evidence

ORD record
ord-e12f2fd503a14d68a7453bc8e84452ed
Source dataset
uspto-grants-2013_09
Patent number
US08536338B2

Reaction notes

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