文献类型：学位论文

中文题名：帕潘立酮的合成

英文题名：Synthesis of Paliperidone

作者：王超[1];

机构：[1]华东理工大学;

导师：冀亚飞;华东理工大学

授予学位：硕士

语种：中文

中文关键词：帕潘立酮;精神分裂症;多巴胺D/_2受体和5-HT/_2受体双重拮抗剂;合成

外文关键词：paliperidone;schizophrenia;dual antagonist of dopamine D/_2 receptors and 5-HT/_2 receptors;synthesize

摘要：帕潘立酮是一种多巴胺D2受体和5-HT2A受体双重拮抗剂,临床主要用于治疗精神分裂症。由两关键中间体3-/(2-氯乙基/)-6,7,8,9-四氢-9-羟基-2-甲基-4H-吡啶/[1,2-a/]嘧啶-4-酮和6-氟-3-/(4-哌啶基/)-1,2-苯并异噁唑盐酸盐缩合反应得到。以2-氨基-3-羟基吡啶为原料,经羟基的苄基化保护反应后与α-乙酰基-γ-丁内酯环合得到3-/(2-羟乙基/)-2-甲基-9-苄氧基-4H-吡啶/[1,2-a/]嘧啶-4-酮,再经氯化、氢化反应得到一种关键中间体3-/(2-氯乙基/)-6,7,8,9-四氢-9-羟基-2-甲基-4H-吡啶/[1,2-a/]嘧啶-4-酮；以4-哌啶甲酸为原料与乙酐反应制得N-乙酰基-4-哌啶甲酸,再经历酰氯化、与间二氟苯Friedel-Crafts酰基化反应得到N-乙酰基-4-/(2,4-二氟苯甲酰基/)哌啶,N-乙酰基-4-/(2,4-二氟苯甲酰基/)哌啶脱保护产物与盐酸羟胺进行缩合反应生成/(2,4-二氟苯基/)-/(4-哌啶基/)甲酮肟盐酸盐,再经分子内环合、成盐步骤得6-氟-3-/(4-哌啶基/)-1,2-苯并异嗯唑盐酸盐。最后,中间体6-氟-3-/(4-哌啶基/)-1,2-苯并异嗯唑盐酸盐与3-/(2-氯乙基/)-6,7,8,9-四氢-9-羟基-2-甲基-4H-吡啶/[1,2-a/]嘧啶-4-酮缩合得到目标产物帕潘立酮。总收率为17.1/%。在羟基的苄基化保护反应中,以甲苯-水替代常用的二氯甲烷-水作为两相反应溶剂,避免了酚羟基与二氯甲烷发生亲核副反应,使副产物得到有效的抑制,并且简化了后处理过程；在3-/(2-羟乙基/)-2-甲基-9-苄氧基-4H-吡啶/[1,2-a/]嘧啶-4-酮氯化的反应中,优化了后处理方法,提高了收率；在/(2,4-二氟苯基/)-/(4-哌啶基/)甲酮盐酸盐与盐酸羟胺的缩合反应中,讨论了回流时间对产物顺反异构体含量的影响,找出了最佳条件；在/(2,4-二氟苯基/)-/(4-哌啶基/)甲酮肟盐酸盐的分子内环合反应中,采用操作简便的相转移催化两相反应,简化了实验操作,提高了收率。 中间体及目标产物的化学结构经MS、1H-NMR确证,并讨论了影响各步反应的主要因素,从中得到合成帕潘立酮较佳的反应条件。
Paliperidone acts as a dual antagonist of dopamine D2 receptors and 5-HT2 receptors, clinically used for the treatment of schizophrenia. It is synthesized by two key intermediates: 3-/(2-chloroethyl/)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido/[1,2-a/]pyrimidin-4-one and 6-fluoro-3-/(4-piperidinyl/)-1,2-benzisoxazole hydrochloride.2-amino-3-hydroxypyridine as a starting material was cyclized withα-acetyl-y-butyrrolactone after hydroxyl group protection to provide 3-/(2-hydroxyethyl/)-2-methyl-9-benzyloxy-4H-pyrido/[1,2-a/]pyrimi-din-4-one, which was subjected to a chlorination reaction followed by a hydrogenation reaction to afford a key intermediate 3-/(2-chloroethyl/)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido/[1,2-a/]pyrimidin-4-one.4-Piperidinecarboxylic acid as a starting material reacted with acetic anhydride to give N-acetyl-4-piperidinecarboxylic acid, which was performed a chlorination reaction followed by a Friedel-Crafts acylation reaction with m-difluorobenzene to provide N-acetyl-4-/(2,4-difluorobenzoyl/)piperidine. The deprotection product of N-acetyl-4-/(2,4-difluorobenzoyl/)piperidine was condensed with hydroxylamine hydrochloride to give /(2,4-difluorophenyl/)-/(4-piperidinyl/)methanone oxime hydrochloride, which was subjected to intramolecular cyclization and then salification to give another key intermediate 6-fluoro-3-/(4-piperidinyl/)-1,2-benzisoxazole hydrochloride. Finally,6-fluoro-3-/(4-piperidinyl/)-1,2-benzisoxazole hydrochloride was condensed with 3-/(2-chloroethyl/)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido/[1,2-a/]pyrimidin-4-one to give paliperidone as title compound. The total yield is 17.1/%. In the reaction 2-amino-3-hydroxypyridine reacted with benzyl chloride to protect hydroxyl group, toluene was used instead of methylene dichloride to prevent nucleophilic side reaction of hydroxyl group with methylene dichloride and the purification process was simplified meanwhile; In the chlorination reaction of 3-/(2-hydroxyethyl/)-2-methyl-9-benzyloxy-4H-pyrido/[1,2-a/]-pyrimidin-4-one, the purification process was optimized and the yield was raised; In the reaction /(2,4-difluorophenyl/)-/(4-piperidinyl/)methanone hydrochloride was condensed with hydroxylamine hydrochloride, the effect of refluxing time on the ratio of Z//E isomers of the product was discussed and the best conditions was found; In the intramolecular cyclization reaction of /(2,4-difluorophenyl/)-/(4-piperidinyl/)methanone oxime hydrochloride, simple phase transfer catalytical system was introduced to simplify the operation process and to improve the yield. The structures of the intermediates and products were confirmed by MS and 1H-NMR spectra. Through a series of experiments and discussion of key factors affecting the reactions, the proper reaction conditions of synthesizing paliperidone was found.