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浙江大学学报(工学版)
浙江大学学报(工学版)
化学工程     
伊潘立酮的合成新工艺
戴颖萍,戴立言,王晓钟,陈英奇
浙江大学 化学工程与生物工程学系,浙江 杭州 310027
Novel process for iloperidone synthesis
DAI Ying-ping, DAI Li-yan, WANG Xiao-zhong, CHEN Ying-qi
Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
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摘要：

开发新合成路线以解决非典型抗精神病药伊潘立酮合成过程中产品纯度低的问题.以(2,4-二氟苯基)-4-哌啶基甲酮盐酸盐为原料,经过肟化、闭环、N-烷基化以及Mitsunobu反应4步制得伊潘立酮. 各步反应条件及收率如下：肟化反应以盐酸羟胺为肟化试剂,在乙醇中回流反应10 h,收率为83.0%；闭环反应在5%的氢氧化钠水溶液中进行,回流1 h,收率为94.5%；以廉价的3-氯丙醇为烷化剂,乙腈为溶剂,在碘化钾催化下进行N-烷基化反应,回流24 h,收率为79.1%；在偶氮二甲酸二异丙酯（DIAD）和三苯基膦作用下进行Mitsunobu反应,反应温度为0 ℃,反应时间为1 h,收率为75.7%. 此工艺操作简便，总收率为47%、产品纯度为99.8%,具有较好的工业应用价值.主要化合物经1H-NMR、HRMS确证结构．
Abstract:

A novel process was developed to solve the problem of low purity of product in the synthesis of iloperidone, which was an atypical antipsychotic drug. The target compound was synthesized starting from 2,4-difluorophenyl-(4-piperidinyl)methanone hydrochloride, via oximation, ring-closure, N-alkylation and Mitsunobu reaction. The optimal reaction conditions were as follows. Oximation reaction which used hydroxylamine hydrochloride as oximation reagent was carried out in ethanol under reflux for 10 h, and 830% yield was obtained. The ring-closure reaction was carried out in 5% NaOH aqueous solution under reflux for 1 h, and 945% yield was obtained. N-alkylation reaction using 3-chloropropanol as alkylation agent, acetonitrile as solvent, and potassium iodide as catalyst was carried out under reflux for 24 h, and 791% yield was obtained. In the presence of diisopropyl azodiformate (DIAD) and triphenylphosphine, Mitsunobu reaction was carried out in ice bath for 1 h, and 757% yield was obtained. This process has great value for industrialization because of convenient operation, total yield (47%) and purity (998%) of product. The structures of  main compounds were confirmed by 1H-NMR, HRMS．
出版日期: 2015-08-28
:  TQ 244.2  
基金资助:

国家自然科学基金资助项目（21176213）；浙江省重点科技创新团队绿色制药工艺科技创新团队资助项目(2010R50043)
通讯作者: 戴立言,男,教授     E-mail: dailiyan@zju.edu.cn
作者简介: 戴颖萍（1988- ）,女,硕士生,从事医药中间体合成研究.E-mail: daiyingping_1211@126.com
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引用本文:

戴颖萍,戴立言,王晓钟,陈英奇. 伊潘立酮的合成新工艺[J]. 浙江大学学报(工学版), 10.3785/j.issn.1008-973X.2015.03.026.

DAI Ying-ping, DAI Li-yan, WANG Xiao-zhong, CHEN Ying-qi. Novel process for iloperidone synthesis. JOURNAL OF ZHEJIANG UNIVERSITY (ENGINEERING SCIENCE), 10.3785/j.issn.1008-973X.2015.03.026.

链接本文:

http://www.zjujournals.com/eng/CN/10.3785/j.issn.1008-973X.2015.03.026    或    http://www.zjujournals.com/eng/CN/Y2015/V49/I3/585

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