Acetic Acid → Entacapone Impurity 55

Participants

Reaction Steps

A flask was charged with 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (20 g, 0.0947 mole) (formula 2 where R is ethyl) and N,N-diethylaminocyanoacetamide (formula (3)) (14.6 g, 0.1042 mol), acetic acid (3.13 g), and piperidine (4.45 g), along with toluene (200 mL), and was heated to a reflux temperature of about 100-115° C. with continuous removal of water azeotrophically for about 15 hours. After the reaction was complete, the reaction mixture was concentrated to a volume of 20-30 mL, quenched into dilute hydrochloric acid and chilled water (200 mL), and stirred for 60 minutes. The precipitated solid was filtered and dried to provide 30 g (95% yield, HPLC purity of 94% (including isomer)) of N,N-diethyl-2-cyano-3-(-3-ethoxy-4-hydroxy-5-nitrophenyl)acrylamide. The product was used as such directly to the next stage. MR=110.0-117.2° C.

Provenance & Evidence