2-Amino-4-methylpyridine → ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate

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Reaction Steps

In this specific example of synthesis of ND-8454, a solution of 2-amino-4-picoline (10.0 g, 91.5 mmol) and ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 mL of 1,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered and solids (2-amino-4-picoline hydrochloride salt) was collected and washed with hexanes. The filtrate liquor was concentrated in vacuo and residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2×) and brine. The organic phase was collected, dried over sodium sulfate (Na2SO4), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 20% ethyl acetate:CH2Cl2 solvent system to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate as a tan solid. mp 59-61° C.; 1H NMR (300 MHz, CDCl3) 9.14 δ(d, J=7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J=7.1, 1.7 Hz, 1H), 4.40 (q, J=7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1.42 (t, J=7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calcd. for C12H15N2O2, 219.1155; found 219.1128. Retention time=1.4 minutes (mobile phase: 60% water:acetonitrile).

Provenance & Evidence