Reaction Steps
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (0.731 g, 3.04 mmol, step 3), 3-bromo-1,1,1-trifluoroacetone (1.3 mL, 13 mmol) and molecular sieves (4.0 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (15 mL) was refluxed for 22.5 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to yield a brown oil which was dissolved in dichloromethane (100 mL) and washed with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude desired 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 1.00 g (99% yield) of 8-[(1-phenylcyclopropyl)methoxy]-2-(trifluoromethyl)imidazo[1,2-α]pyridine (Rf=0.33 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of the free amine (0.950 g, 2.86 mmol) in dichloromethane (4 mL) and anhydrous diethyl ether (16 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. After 20 min, the solvent was removed in vacuo, and the residue was triturated in anhydrous diethyl ether to give the title compound as a pale yellow solid (0.414 g, 39% yield). 1H-NMR (300 MHz, CDCl3) δ 8.58 (d, 1H, Ar), 8.55 (s, 1H, Ar), 7.50 (m, 1H, Ar), 7.06 (m, 2H, Ar), 6.91 (m, 2H, Ar), 6.78 (m, 1H, Ar), 6.72 (d, 1H, Ar), 4.11 (s, 2H, CH2O), 0.69 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 146.50 (+), 141.44 (+), 137.01 (+), 129.76/129.21 (+), 127.90 (−), 125.98 (−), 121.69/118.12 (+), 120.97 (−), 116.31 (−), 114.85 (−), 107.82 (−), 76.35 (+), 23.03 (+), 13.75 (+); LRMS-FAB m/z: MH+ 333 (100%); Anal. calcd for C18H15N2OF3.HCl: C, 58.63; H, 4.37; N, 7.60%. found: C, 56.80; H, 4.07; N, 7.03%.
