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

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Reaction Steps

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.

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