Acetic Acid → Entacapone Impurity 9

Participants

Reaction Conditions

Reaction Steps

A flask was charged with 3-methoxy-4-hydroxy-5-nitrobenzaldehyde (25 g, 0.126 mole) (formula 2 where R is methyl) and N,N-diethylaminocyanoacetamide (formula (3)) (22.2 g, 0.158 mole), acetic acid (4.18 g) and piperidine (5.94 g), along with toluene (250 mL) and was heated to a reflux temperature of about 105-110° C. Water was removed azeotrophically for 15 hours. The reaction mixture was concentrated and quenched into dilute hydrochloric acid and chilled water (375 mL), and stirred for 3 hours. The precipitated solid was filtered and dried to provide 36 g (88.95% yield, HPLC purity of 94.2% (including isomer)) of the N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)acrylamide, which was used as such for the next stage.

Provenance & Evidence