Synthesis Of Iloperidone And Its Analogues

Iloperidone is a mixed dopamine D2/serotonin5-HT2A receptor antagonist, which acts as an atypical antipsychotic drug for the treatment of schizophrenia in adults.In this paper, a novel process was developed for synthesizing iloperidone on the basis of reported literatures, and the target compound was obtained starting from2,4-difluorophenyl-(4-piperidinyl)methanone hydrochloride, via oximation, cyclization, N-alkylation, Mitsunobu reaction. The effect of reaction parameters, including time, temperature, solvents, catalysts, molar ratios of materials in each step on yields was investigated in detail, and the optimal reaction conditions were obtained. Oximation reaction was carried out in ethanol under reflux for10h, and83.0%yield was obtained. The cyclization reaction was carried out in5%NaOH aqueous solution under reflux for1h, and94.5%yield was obtained. N-alkylation reaction which used3-chloropropanol as alkylating agent, acetonitrile as solvent, and potassium iodide as catalyst was carried out under reflux for24h, and79.1%yield was obtained. In the presence of diisopropyl azodiformate (DIAD) and triphenylphosphine, Mitsunobu reaction was carried out in ice bath for1h, and75.7%yield was obtained. This process has great value for industrialization because of convenient operation, moderate yield, and high purity.In the new method for synthesizing iloperidone, the key step is the Mitsunobu reaction between6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole and4-hydroxy-3-methoxyacetophenone. A series of iloperidone analogues were synthesized by this method. The effects of nucleophilic reagents with different substituents on Mitsunobu reaction were also studied. The result showed that the yields of Mitsunobu reaction were affected by both electron-induced effect and steric hindrance of substituents on the benzene rings. Furthermore, the iloperidone analogues were evaluated for antipsychotic activities in vitro. Based on the preliminary test, the structure-activity relationship was discussed. The structures of the main compounds obtained above were confirmed by1H-NMR, HRMS.