Reaction Steps
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.84 g, 3.50 mmol, see example 23), 1-bromo-3-methyl-2-butanone (0.69 g, 4.2 mmol) and molecular sieves (4.2 g, type 4 Å, beads, 8–12 mesh) in anhydrous ethanol (10 mL) was refluxed for 24 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (20 mL) and then extracted with ethyl acetate (3×40 mL). The organic extracts were combined, washed with water (2×5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel filled with 300 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylamine) yielded 0.814 g (76% yield) of 2-isopropyl-8-[(1-phenyl-cyclopropyl)methoxy]imidazo[1,2-α]pyridine as a free base (Rf=0.60 in ethyl acetate-hexanes, 1:1 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.755 g, 2.46 mmol) in anhydrous diethyl ether (10 mL) was treated with ethereal hydrogen chloride (50 mL) to form the hydrochloride salt. After 1 h, the solvent was decanted and the title compound was isolated as a solid (0.844 g, quantitative). 1H-NMR (300 MHz, CDCl3) δ 15.59 (br s, 1H, +NH), 8.36 (m, 1H, Ar), 7.85 (d, 1H, Ar), 7.63 (d, 2H, Ar), 7.24 (m, 2H, Ar), 7.13 (m, 1H, Ar), 7.01 (t, 1H, Ar), 6.74 (d, 1H, Ar), 4.29 (s, 2H, CH20), 3.64 (m, 1H, CH), 1.40 (d, 6H, 2CH3), 1.12 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 145.64 (+), 144.89 (+), 142.33 (+), 133.36 (+), 130.04 (−), 128.27 (−), 126.78 (−), 120.09 (−), 116.68 (−), 110.31 (−), 109.82 (−), 77.99 (+), 25.51 (−), 25.45 (+), 21.99 (−), 11.45 (+); LRMS-ES m/z: MH+ 307.3.
