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CN115611828A - 一种阿立哌唑关键中间体ii的制备方法 - Google Patents

一种阿立哌唑关键中间体ii的制备方法 Download PDF

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CN115611828A
CN115611828A CN202110799003.6A CN202110799003A CN115611828A CN 115611828 A CN115611828 A CN 115611828A CN 202110799003 A CN202110799003 A CN 202110799003A CN 115611828 A CN115611828 A CN 115611828A
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aripiprazole
key intermediate
synthetic method
preparation
ring
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罗米海
郭夏
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种阿立哌唑关键中间体II的制备方法，一种如以下结构式(II)的阿立哌唑关键中间体化合物的制备方法，其特征在于以下步骤：以市售的二乙醇胺为起始物料，一锅法经过氯代以及关环合成关键中间体II。本发明制备的阿立哌唑中间体后处理方法简单、纯度高，适合工业化生产。

Description

一种阿立哌唑关键中间体II的制备方法
技术领域本发明属于药物化学领域，具体涉及一种精神分裂症药物阿立哌唑关键中间体的制备方法。
背景技术
阿立哌唑是一种非典型抗精神分裂症药物，对DA能神经系统具有双向调节作用，是DA递质的稳定剂。与D2、D3、5-HT1A和5-HT2A受体有很高的亲和力。通过对D2和5-HT1A受体的部分激动作用及对5-HT2A受体的拮抗作用来产生抗精神分裂症作用的，用于治疗各类型的精神分裂症。英文化学名：7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone。
其分子式如下：
Figure 450436DEST_PATH_IMAGE001
专利CN89108934.9中首次公开了如下所示的制备阿立哌唑的方法。
Figure 264808DEST_PATH_IMAGE002
式中X为Cl、Br、I。
对于关键中间体II的合成一直存在问题，它的合成至关重要。
多篇文献报道了中间体II的制备方法。文献Tetrahedron Lett. 2002, 43, 3359.
在催化剂条件下，使用过量的碱来制备中间体II，之后在HCl气体下成盐
Figure 87271DEST_PATH_IMAGE003
Tetrahedron Letters 46 (2005) 7921–7922中报道了；在二乙醇单甲醚为溶剂、加热至150oC条件下伯胺与二氯乙胺关环反应得到目标产物，但其后处理需要乙醚洗涤，之后盐酸成盐，后处理麻烦产品收率低，纯度低。
Figure 354304DEST_PATH_IMAGE004
以上专利中报道的式II化合物的制备方法，都不适合放大，而且原子经济性差，过量的碱以及特殊的溶剂。所以，寻找一种合适的反应时试剂，反应条件是至关重要。
发明内容
本发明提供了一种两步法制备阿立哌唑关键中间体II的方法，以市售的二乙醇胺为起始物料，一锅法经过氯代以及关环合成关键中间体II。本发明制备的阿立哌唑中间体后处理方法简单、纯度高，适合工业化生产。
Figure 615521DEST_PATH_IMAGE005
在合成方法；所述的卤代试剂选自二氯亚砜、三氯化磷。
在合成方法;所述的卤代反应溶剂选自乙酸乙酯
合成方法；关环的试剂为丙三醇、环丁砜。
合成方法；关环温度为160-200oC。

Claims (5)

1.一种如以下结构式(II)的阿立哌唑关键中间体化合物的制备方法，其特征在于以下步骤：以市售的二乙醇胺为起始物料，一锅法经过氯代以及关环合成关键中间体II。
Figure DEST_PATH_IMAGE001
2.根据权利要求1所述的合成方法;所述的卤代试剂选自二氯亚砜、三氯化磷。
3.根据权利要求1所述的合成方法;所述的卤代反应溶剂选自乙酸乙酯。
4.根据权利要求1所述的合成方法；关环的试剂为丙三醇、环丁砜。
5.根据权利要求1所述的合成方法；关环温度为160-200oC。
CN202110799003.6A 2021-07-15 2021-07-15 一种阿立哌唑关键中间体ii的制备方法 Pending CN115611828A (zh)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1042537A (zh) * 1988-10-31 1990-05-30 大制药株式会社 喹诺酮衍生物
US20080299216A1 (en) * 2007-06-01 2008-12-04 Protia, Llc Deuterium-enriched aripiprazole
CN101560178A (zh) * 2009-05-22 2009-10-21 中国药科大学 一种多取代吲哚啉类化合物、其制备方法及医药用途
US20100069399A1 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceutical, Inc. Arylpiperazine modulators of d2 receptors, 5-ht1a receptors, and/or 5-ht2a receptors
CN108299337A (zh) * 2018-01-15 2018-07-20 吴江信凯医药科技有限公司 一种2，3-二氯苯基哌嗪盐酸盐的制备方法
CN109810076A (zh) * 2017-11-21 2019-05-28 盘锦格林凯默科技有限公司 一种1-（2，3-二氯苯基)哌嗪盐酸盐的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1042537A (zh) * 1988-10-31 1990-05-30 大制药株式会社 喹诺酮衍生物
US20080299216A1 (en) * 2007-06-01 2008-12-04 Protia, Llc Deuterium-enriched aripiprazole
US20100069399A1 (en) * 2008-09-15 2010-03-18 Auspex Pharmaceutical, Inc. Arylpiperazine modulators of d2 receptors, 5-ht1a receptors, and/or 5-ht2a receptors
CN101560178A (zh) * 2009-05-22 2009-10-21 中国药科大学 一种多取代吲哚啉类化合物、其制备方法及医药用途
CN109810076A (zh) * 2017-11-21 2019-05-28 盘锦格林凯默科技有限公司 一种1-（2，3-二氯苯基)哌嗪盐酸盐的制备方法
CN108299337A (zh) * 2018-01-15 2018-07-20 吴江信凯医药科技有限公司 一种2，3-二氯苯基哌嗪盐酸盐的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
朱晓斌;徐崇福;陈苗;: "一锅法制备1-(2, 3-二氯苯基)哌嗪盐酸盐", 江苏工业学院学报, no. 04, 25 December 2008 (2008-12-25), pages 32 - 35 *
赵文环;王莉;张晓红;: "1-(2, 3-二氯苯基)哌嗪盐酸盐合成工艺改进", 精细化工中间体, no. 02, 28 April 2017 (2017-04-28), pages 56 - 57 *

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