Triethylamine → N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-ethoxy-phenyl)-4-methyl-nicotinamide

Participants

Reaction Steps

4-Methyl-nicotinic acid hydrochloride (0.83 g, 4.8 mmol) was suspended in CH2Cl2 (25 mL) with DMF (6 drops). Oxalyl chloride (2.5 mL, 28.8 mmol) was added and the mixture stirred at room temperature for 2 h. The homogenous solution was then concentrated and dried in vacuo. To the solid was added THF (12.5 mL) and a solution of (R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile (0.69 g, 2.4 mmol) in THF (12.5 mL). The mixture was treated with Et3N (1.0 mL, 7.2 mmol) and heated to reflux, stirring for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (100 mL) and washed with brine solution (100 mL). The aqueous phase was back-extracted with CH2Cl2 (100 mL) and the combined organic phases rewashed with brine (200 mL). The organic phase was dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (10:1 Et2O/MeOH to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-ethoxy-phenyl)-4-methyl-nicotinamide contaminated with nicotinyl chloride by-product (24%).

Provenance & Evidence