Chloroacetaldehyde → Methyl imidazo(1,2-a)pyridine-7-carboxylate

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Reaction Steps

Methyl 2-aminoisonicotinate (5.64 g) and chloroacetaldehyde (6.1M, 12.2 mL) were dissolved in EtOH. To this solution, sodium hydrogen carbonate (6.23 g) was added and heated to 80 degrees. After stirring for 2 hours, the reaction mixture was evaporated and treated with water, extracted ethyl acetate, washed with brine, dried over sodium sulfate, then evaporated under reduced pressure to give methyl imidazo[1,2-a]pyridine-7-carboxylate (4.42 g). This compound (4.42 g) was dissolved in acetic acid. To this solution, formaldehyde (37%, 13.2 mL) and sodium acetate (7.82 g) were added and heated to 105 degrees. After stirring for 3 hours, the reaction mixture was treated with water, and NaOH aq., then the precipitate was filtered off. The filtrate was extracted with EtOAc-n-BuOH (×2), dried over sodium sulfate, then evaporated under reduced pressure to give methyl 3-(hydroxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (2.22 g). This compound (2.22 g) was dissolved in N,N-dimethylformamide, to the solution, diphenylphosphoryl azide (6.14 g) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.40 g) were added. After stirring for 2 hours at room temperature, the reaction mixture was evaporated, and then treated with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-(azidomethyl)imidazo[1,2-a]pyridine-7-carboxylate (1.91 g). This compound (1.91 g) was dissolved in THF (30 mL) and water (3 mL). To this solution, triphenylphosphine (4.33 g) was added and heated to 70 degrees. After stirring for 1.5 hours, the reaction mixture was evaporated and treated with 1N HCl. The water phase was washed with EtOAc (×2) to give methyl 3-(aminomethyl)imidazo[1,2-a]pyridine-7-carboxylate 2 hydrochloride (1.98 g).

Provenance & Evidence