Synthesis Of Risperidone And Paliperidone As Anti-schizophrenia Dugs And N-heterocyclic Carbene-palladium(Ⅱ)-pyridine Complex Catalyzed Heck Reaction

This paper consists of two parts:the synthesis of risperidone and paliperidone as anti-schizophrenia drugs and the Heck reaction catalyzed by NHC-Pd（Ⅱ）-Py catalyzed.Part 1:Synthesis of anti-schizophrenia drugs risperidone and paliperidone.Risperidone and paliperidone（9-hydroxyrisperidone）were developed by Janssen Pharmaceuticals,which are the second-generation antipsychotic drug.Their mechanism of action are dual antagonism of central dopamine 2（D₂）receptors and serotonin 2(5HT_2A)receptors.Risperidone and Paliperidone can be used to treat acute and chronic schizophrenia and other obvious positive and negative symptoms.Compared with typical antipsychotics,these drugs have a lower tendency to cause extrapyramidal symptoms（EPS）and no substained elevation of prolactin.And They are safe and well tolerated.They have been approved by the FDA for the treatment of schizophrenia.Risperidone and paliperidone mainly involve three important intermediates synthesis:3-（2-chloro-ethyl）-2-methyl-6,7,8,9-tetrahydro-4H-pyridine[1,2-a]pyrimidin-4-one（11）,3-（2-chloroethyl）-9-hydroxy-2-meth-yl-6,7,8,9-tetrahydro-4H-pyridine[1,2-a]pyrimidin-4-one（31）and 6-fluoro-3-（4-piperidinyl）-1,2-benzisoxazole（6）.This research mainly synthesizes intermediates 11 and 31,and innovatively designs a reasonable synthetic route that ethyl acetoacetate is alkylated with 1-bromo-2-chloroethane,and then bimolecular cycloaddition with 2-aminopyridine（3-hydroxy-2-amino-pyridine）,and catalytic hydrogenation to obtain key intermediates 11 and31,and finally combined with intermediate 6 to obtain the target compounds risperidone and paliperidone.Part 2:NHC-Pd（Ⅱ）-Py complex catalyzed Heck reaction.Stilbene analogs are important pharmacophores in natural products,bioactive molecules and drugs.This research group proposed that NHC-Pd（Ⅱ）-Py catalyzed the Heck coupling reaction of aromatic bromine and olefin derivatives to prepare stilbene analogs.The catalytic system is simple,gentle and well tolerated,and various stilbene derivatives can be prepared with excellent yields under solvent-free conditions.