Schizophrenia Drug Palmer Pan Li Ketone Synthesis Process Research

Paliperidone is an antipsychopathy drug,a metabolite with antipsychopathy activity from risperidone through liver catalyzed by P450 rase.Paliperidone has less side effects than risperidone and its half life is eight times higher than risperidone.Asychopathy’s action mechanism,curation, the development use of antipsychopathy drug,were introduced briefly as well as paliperidone’s action mechanism,clinical usage,development condition and application perspectives.Paliperidone was prepared from intermediates 3-(2-chloroethyl)-9-hydroxyl-2-methyl -6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one(Ⅰ)and 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxa -zole hydrochloride(Ⅱ).The intermediate 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazolehydro -chloride(Ⅱ)was the same intermediate for the synthesis of risperidone.There are many references for its synthesis.The process was studied maturely through 6 steps procedure started from material 4-peperidine methanoic acid and 1,3-diflurobenzene.But the references for the synthesis of the intermediate 3-(2-chloroethyl)-9-hydroxyl-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4 -one(Ⅰ)is few,the route for synthesis of the intermediate 3-(2-chloroethyl)-9-hydroxy -2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one(Ⅰ)was studies mainly.The methods to synthesize the intermediate 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a] pyrimidin-4-one(Ⅰ)were tried many times and failed Finally,a new route was designed and achieved for the synthesis of the intermediate 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahy -dropyrido[1,2-a]pyrimidin-4-one(Ⅰ).It was prepared through the condensation and cyclization of 3-hydroxy-2-aminopyrimidine and a-acetyllaction and then catalyzing reduction following a selective chlorolization.The final product paliperidone was given by condensation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one(Ⅰ)and 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazolehydrochl-oride(Ⅱ).Its structure was characterized by ~1H-NMR and MS.The total yield was 27.6%from the starting material 4-piperiding methanoic acid. All the reactions involving the synthesis of the target molecule are mild and easily handle.The process is easy to scale up in industry.