2-(4-methoxybenzyloxy)-3-bromo-4-methylpyridine synthesis

Yield:1003312-15-9 90%

Reaction Conditions:

Stage #1: 4-Methoxybenzyl alcoholwith sodium hydride in tetrahydrofuran at 20; for 0.5 h;
Stage #2: 3-bromo-2-chloro-4-methylpyridine in tetrahydrofuran at 75; for 6 h;Sealed tube;

Steps:

7

3-Bromo-2-(4-methoxybenzyloxy)-4-methylpyridine
3-bromo-2-(4-methoxybenzyloxy)-4-methylpyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065.
A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion).
To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml).
After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloro-4-picoline (4.97 g, 24.08 mmol) in anhydrous THF (15 ml) was added.
The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours.
Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water.
The separated organic layer was washed with water, sat'd NaCl_(aq.), dried over MgSO₄, filtered, and concentrated.
Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave the title compound as a clear oil which crystallized on standing (6.71 g, 90%).

References:

US2016/96832,2016,A1 Location in patent:Paragraph 0203; 0204