Citric Acid → Agomelatine citric acid

Participants

Reaction Conditions

Reaction Steps

100 g N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide was slurried in 400 ml ethyl acetate at room temperature and heated to reflux to dissolve the entire solid. The solution was cooled to 60° C. and a solution of 78.9 g anhydrous citric acid dissolved in 300 ml methanol was added. The solution was concentrated by distillation to approximately half its volume then cooled to a temperature in the range 2-5° C. and 140 mg of seed crystals prepared by evaporation of a methanolic solution of agomelatine and citric acid were added. Precipitation was observed and a thick white slurry was formed during stirring for 1 hour. The white solid was isolated by filtration and washed with 100 ml ethyl acetate, the final yield of dry material was 97 g (54%) and the purity of agomelatin in the solid was 99.6% with no impurities above 0.4% by UPLC. The isolated solid gave the XRPD pattern shown in FIG. 1, the DSC thermograph shown in FIG. 2 with an onset of melting of approximately 123.5° C. and the Raman spectrum shown in FIG. 3.

Provenance & Evidence