Acetic Acid → Methyl 5-chloro-2-(pyridin-3-yl)nicotinate

Participants

Reaction Steps

To a solution of methyl 3-oxo-3-pyridine-3-ylpropanoate (1-1, 12.50 g, 69.76 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (12.52 g, 111.62 mmol) and stirred for 45 minutes as the reaction temperature reached room temperature. N-[(2Z)-2-chloro-3-(dimethylamino)prop-2-en-1-ylidene]-N-methylmethanaminium hexafluorophosphate (53.46 g, 174.40 mmol) was then added in one portion to the reaction mixture and the system was stirred for 45 minutes. The resulting slurry was then added in one portion to a solution of trifluoroacetic acid (4.14 mL, 55.81 mmol) and acetic acid (27.95 mL, 488.33 mmol) in tetrahydrofuran (100 mL) and stirred for 45 minutes. Ammonium hydroxide (40.75 mL, 1046 mmol) was then added to the reaction mixture and the system was stirred at 90° C. for 3 h. The reaction was then cooled to room temperature, poured into an Erlenmeyer flask and dried over magnesium sulfate. The reaction mixture was filtered and purified via normal phase (1% MeOH in DCM) and reverse phase chromatography (5%→95% 0.1% TFA in water: 0.1% TFA in ACN), followed by subsequent free-basing with saturated sodium carbonate to afford the title compound as a cream solid (1-2). ESI+ MS [MH]+C12H9ClN2O2=248.9.

Provenance & Evidence