GB2563858A — New route of synthesis for opicapone

USPTO Abstract

A process for the preparation of opicapone ((4Z)-4-[3-(2,5-dichloro-4,6-dimethyl-1-oxidopyridin-1-ium-3-yl)-2H-1,2,4-oxadiazol-5-ylidene]-2-hydroxy-6-nitrocyclohexa-2,5-dien-1-one) or a pharmaceutically acceptable salt thereof, the process at least comprises the reaction of 2,5-dichloro-N-hydroxy-4,6-dimethylnicotinimidoyl chloride (formula 6) and 4-hydroxy-3-methoxy-5-nitrobenzonitrile (formula 8) in the presence of a solvent, preferably and aromatic solvent, and a base. Preferably the reaction of the compound of formula 6 with the compound of formula 8 is performed at a temperature of ≥80ºC and ≤140ºC. The base may be a tertiary amine such as triethylamine. The product of the reaction between a compound of formula 6 and a compound of formula 8 is a compound of formula 9 (4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol) which may be de-methylated to form a compound of formula 10 (5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-)1,2,4-oxadizol-5-yl)-3-nitrobenzene-1,2-diol) which may be N-oxidised, preferably in the presence of hydrogen peroxide and trifluoroacetic anhydride, to form opicapone.