Synthesis Of Paliperidone

Paliperidone acts as a dual antagonist of dopamine D2 receptors and 5-HT2 receptors, clinically used for the treatment of schizophrenia. It is synthesized by two key intermediates: 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride.2-amino-3-hydroxypyridine as a starting material was cyclized withα-acetyl-y-butyrrolactone after hydroxyl group protection to provide 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[1,2-a]pyrimi-din-4-one, which was subjected to a chlorination reaction followed by a hydrogenation reaction to afford a key intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.4-Piperidinecarboxylic acid as a starting material reacted with acetic anhydride to give N-acetyl-4-piperidinecarboxylic acid, which was performed a chlorination reaction followed by a Friedel-Crafts acylation reaction with m-difluorobenzene to provide N-acetyl-4-(2,4-difluorobenzoyl)piperidine. The deprotection product of N-acetyl-4-(2,4-difluorobenzoyl)piperidine was condensed with hydroxylamine hydrochloride to give (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride, which was subjected to intramolecular cyclization and then salification to give another key intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride. Finally,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride was condensed with 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one to give paliperidone as title compound. The total yield is 17.1%. In the reaction 2-amino-3-hydroxypyridine reacted with benzyl chloride to protect hydroxyl group, toluene was used instead of methylene dichloride to prevent nucleophilic side reaction of hydroxyl group with methylene dichloride and the purification process was simplified meanwhile; In the chlorination reaction of 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[1,2-a]-pyrimidin-4-one, the purification process was optimized and the yield was raised; In the reaction (2,4-difluorophenyl)-(4-piperidinyl)methanone hydrochloride was condensed with hydroxylamine hydrochloride, the effect of refluxing time on the ratio of Z/E isomers of the product was discussed and the best conditions was found; In the intramolecular cyclization reaction of (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride, simple phase transfer catalytical system was introduced to simplify the operation process and to improve the yield.The structures of the intermediates and products were confirmed by MS and 1H-NMR spectra. Through a series of experiments and discussion of key factors affecting the reactions, the proper reaction conditions of synthesizing paliperidone was found.