Synthesis Study Of Antipsychotic Iloperidone

Psychosis, is a kind of mental incompetence, abnormal behavior as the main features of the disease with high rate of disability, which always falls in youth, some breaks out intermittently, some is sustained seizures, and gradually tends to be chronic. It is difficult for the patients to assume the responsibility for the family and society. In recent years, people’s spiritual pressure is growing with the accelerated pace of life. The quantity of psychiatric patients is becoming bigger and bigger. With such a serious situation, the study and development of antipsychotics are of great significance.Iloperidone, whose chemical name is 1-(4-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl)propoxy-3-methoxyphenyl)ethanone, was developed by the US Vanda Pharma company and listed for the first time in the United States in May, 2009. And it can declare 3.1 class of new drugs if developed successfully which has not been listed in China at present. As a new atypical antipsychotic, it is not only effective against the positive symptoms of schizophrenia, but also has particularly prominent effect to negative symptoms. Compared with the other antipsychotics, it has fewer side effects, such as EPS, and no akathisia, less cognitive decline. Meanwhile it can less induce diabetes and somnolence.The thesis mainly focuses on the process study of iloperidone. The related references show that the preparation of iloperidone mainly includes the synthesis of two intermediates, namely 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 4-(3-chloride propoxyl)-3-methoxy acetophenone. At the same time, most of the references use some raw materials which are complex and difficult to get to prepare the final product iloperidone. So, a new, simple, total synthetic route which has lower cost and less operation steps was got on the basis of the route which has been reported. Piperidine-4-carboxylic acid and 4-hydroxy-3-methoxy acetophenone with simple structure and easy availability were used as the starting materials. And the one-pot method was used to make the experimental operation simple.Starting with piperidine-4-carboxylic acid, acetic acid and acetic anhydride, 2,4-difluorophenyl-(1-acetyl-4-piperidinyl)methanone 4 was synthesized by amidation, chlorination reaction and Friedel-Crafts acylation, then oximation with hydroxylamine hydrochloride followed by intramolecular cyclization, deprotection of amination to afford intermediate 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride 5; Another intermediate was offered by O-alkylation of 4-hydroxy-3-methoxy acet- ophenone, without isolation which then condensed with the compound 5 to afford iloperidone. Reaction conditions of each step were optimized to make the total yield of the route reach to 46.7%. Such as, the feeding mode of Friedel-Crafts acylation was changed to guarantee a higher conversion rate and it can avoid bringing about a lot of heat which may influence the reaction; Then using the one-pot method to get the intermediate 5 which can make the procedure and operation simpler. The process had the cheap raw materials, mild condition, simple operation to make it more suitable for the industrial scale production.The chemical structure of iloperidone and its important intermediates were confirmed by 1H-NMR and MS.