Study On The Preparation Of The Iloperidone

Mankind enters the 21st century, mental illness is flooding in the world. In China, the number of schizophrenia patients is upto 49%. With the rising number of schizophrenia patients every year, the antischizophrenic drugs is considerably demanded. A series of novel antischizophrenic drugs is on the market in recent years, for example, risperidone and olanzapine, they have been widely used in the treatment of various types of schizophr-enia, more effective than conventional antipsychotic drugs. Though the safety of new anti-schizophrenic drugs has been increased, but they have some passive effect, it needs to take medicine for long time and leads the illness to recurrence frequently. So it is necessary to the appearance of a new target for drugs. Iloperdone, the first gene targeting of a typical antipsychotics, that is 5-HT2/D2 receptor antagonist, and it is a new drug approved by the FDA in May 2009. The synthetic route of iloperdone is systematically studied in this paper.In the paper, three synthetic routes are designed for iloperdone, the suitable synthet-ic route is got through the experiment, that is,4-(2,4-difluorobenzoyl)piperidine hydrochl-oride is designed as the starting material, through oximation and neutralization to obtain (Z)-4-(2,4-difluorobenzoyl)piperidine oxime, it reacts with 1-[4-(3-chloropropoxy)-3-me-thoxyphenyl]ethanone through one step to obtain the targeted compound, the yeild of this step is 65.00%, and the purity of the iloperdone is upto 99.98%.The synthetic route of 4-(2,4-difluorobenzoyl)piperidine hydrochloride is explored. The conclution is that the best synthetic route is with 1-acetyl-4-piperidinecarboxylic acid as the starting material, via ac-ylation, chlorination, Friedel-Crafts acylation and hydrolyzation to afford 4-(2,4-difluoro-benzoyl)piperidine hydrochloride. The total yield of four steps is 41.11%. The synthesis of intermediate 1-(4-(3-chloropoxy)-3-methoxyphenyl)ethanone is also studied, the conclusi-on is that 1-(4-hydroxy-3-methoxyphenyl)ethanone reacts with 1-bromo-3-chloropropane to afford the intermediate. Post-processing method is to use vacuum distillation to obtain the product. After the recrystallization of ethyl acetate and hexane, the purity is 95.54% and the yield is 81.66%.In view of the cheap available materials and simple operations, the synthetic process is suitable for large-scale manufacture.The structures are confirmed through IR, NMR and MS.