Thionyl Chloride → 5-(Chloromethyl)-2-methylpyridine

Participants

Reaction Conditions

Reaction Steps

To a solution of (6-methyl-3-pyridyl)-methanol (50 g, 0.506 mol) in toluene (500 ml) and water (9 ml) at 35° C. under nitrogen was added thionyl chloride (66.9 ml, 1.06 mol) dropwise After stirring at 35° C. overnight 300 ml was distilled off under vacuum and rediluted with toluene (250 ml) and water (10 ml) to give a solution of 5-chloromethyl-2-methyl-pyridine (J. Med. Chem, 2004, 47(11), 4787). The mixture was then heated to 40° C. and morpholine (112.2 ml, 1.29 mol) added and the slurry heated to 80° C. for 3 hrs. After cooling to room temperature saturated sodium carbonate solution (150 ml) was added and the aqueous phase separated and extracted with toluene (200 ml). The combined organic layer was washed with brine and concentrated. The oil was dissolved in iso-octane (300 ml) at 40° C. then cooled to −5° C. overnight. Two crops were obtained which gave 53.65 g, 72% yield of 4-[(6-methylpyridin-3-yl)methyl]morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR: (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.

Provenance & Evidence