An Investigation into Formation of Impurities During Synthesis of Blonanserin

Abstract

hexahydrocycloocta[b]pyridine) is a novel antipsychotic agent, researched and developed by the Japanese Zhu You Pharmaceutical Co Ltd. and was marketed for the first time in Japan in April 2008. Dopamine D 2 and serotonin 5-HT 2A receptor antagonist properties 1-6. It is one of the secondgeneration antipsychotic agents, together with risperidone and olanzapine, it is effective in the treatment of both positive and negative symptoms of schizophrenia without extra-pyramidal symtoms, but has original properties of affinity higher for the dopamine D 2 receptor than for the serotonin 5-HT 2A receptor 7. On the other hand, blonanserin is much less potent in adrenergic-α 1 , histamine H 1 and muscarinic M 1 antagonist activities 6. Such a pharmacological profile shows that blonanserin is more specific to the dopamine D 2 and serotonin 5-HT 2A receptors with fewer side effects; its excellent effects on schizophrenia have been reported in many reports 8-10. There is a possibility that this drug gain popularity for treatment of schizophrenia throughout the world. In the literature, references, carry out cyclization using 4-fluorobenzoylacetonitrile (4) and cyclooctanone in the presence of polyphosphoric acid (PPA) to get 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(1H)-one (3), yield 60 %. Undergo chlorination of 3 to get 2-chloro-4-(4fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (2), finally carry out substitution reaction with N-ethylpiperazine to get 1. Total yield is 24.4 %.

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N -heterocycles

“…Blonanserin, an atypical antipsychotic approved for treatment of schizophrenia in Asia, undergoes extensive oxidative CYP450 metabolism ( 10 , 11 ). In order to confirm aliphatic oxidation at C7 and C8 on the cyclooctyl ring, independent 5 to 9 step de novo syntheses were needed.…”

“…Functionality at methylene sites is generally incorporated via lengthy de novo syntheses due to the nonpreparative nature of biotransformations ( 5 , 6 ) and the sparsity of chemical methods for such chemoselective oxidations ( 7 , 8 ) ( Fig. 1 C and D ) ( 9 – 11 ).…”