Reaction Steps
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL, 47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (55 mL) was refluxed for 39 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (200 mL) and then washed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel with 450 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 isopropylarnine) afforded 0.352 g (8.6% yield) of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (Rf=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) and anhydrous diethyl ether (3 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo gave a residue which was triturated in anhydrous diethyl ether to afford the title compound as an off-white solid (0.168 g, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 16.91 (br s, 1H, +NH), 9.05 (d, 1H, Ar), 7.65 (d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH3CH2), 4.32 (s, 2H, CH2O), 3.03 (s, 3H, CH3), 1.42 (t, 3H, CH3CH2), 1.15 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 159.49 (+), 145.10 (+), 143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−), 120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+), 25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH+ 351 (100%); Anal. calcd for C21H22N2O3.HCl: C, 65.20; H, 5.99; N, 7.24%. found: C, 64.87; H, 5.96; N, 7.20%.
