Description
Blonanserin, a dual antagonist of dopamine D2 and serotonin 5-HT2 receptors, was launched past year in Japan for the oral treatment of psychosis and schizophrenia. It is the latest entry in the class of atypical antipsychotic agents to reach the market. Blonanserin exhibits high affinity for D2 and 5-HT2 receptors (IC50 23.6 and 9.85 nM, respectively). Its affinity for D2 receptors is very close to that of haloperidol and risperidone, whereas the affinity for 5-HT2 receptors is about 7 times higher than that of haloperidol and 10 times lower than that of risperidone.Blonanserin is chemically derived in three steps starting with a polyphosphoric acid mediated condensation reaction of cyclooctanone with 4-fluorobenzoylacetonitrile. The resultant 4-fluorophenylcycloocta[b]pyridin-2-one intermediate is converted to the corresponding 2-chloro derivative by treatment with phosphoryl chloride and subsequently condensed with 1-ethylpiperazine to afford blonanserin.
Manufacturing Process
Preparation of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-
hexahydrocyclooc ta[b]pyridine:
A mixture of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta
[b]pyridine (2.0 g), N-ethylpiperazine (2.4 g), and potassium iodide (1.1 g) is
stirred at 170°C for 5 hours. After cooling, the reaction mixture is dissolved in
ethyl acetate and water. The organic layer is washed with water and extracted
with 5% hydrochloric acid. The extract is made alkaline with potassium
carbonate, and extracted with ethyl acetate. The extract is washed with water,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure.
(a) The residue is recrystallized from acetonitrile to give the desired product
(1.2 g), MP: 123°-124°C.
This product obtained in the above (a) is converted to the following salt
thereof by treating the product with various acids.
