CN110790704A - 一种月桂酰阿立哌唑的制备方法 - Google Patents

一种月桂酰阿立哌唑的制备方法 Download PDF

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CN110790704A
CN110790704A CN201810863547.2A CN201810863547A CN110790704A CN 110790704 A CN110790704 A CN 110790704A CN 201810863547 A CN201810863547 A CN 201810863547A CN 110790704 A CN110790704 A CN 110790704A
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compound
inorganic base
aripiprazole
alkali metal
formula
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齐晓溪
李恩民
赵国磊
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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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种化学药物——月桂酰阿立哌唑(式I)的合成方法。用7‑[（4卤丁基）‑2‑氧‑3,4‑二氢喹啉酮‑1（2H）‑基]甲基十二烷酸酯经一步反应制得月桂酰阿立哌唑。该方法收率高，且纯度可以达到99.5%以上。

Description

一种月桂酰阿立哌唑的制备方法
技术领域
本发明属于药物化学领域，涉及一种化学药物月桂酰阿立哌唑的制备方法。
背景技术
桂酰阿立哌唑，化学名为7-{4-[4-（2,3-二氯苯基-1-哌啶基）丁氧基] - 2-氧-3,4-二氢-2(1H)-喹啉酮-1-基}甲基十二烷酸酯，英文名Aripiprazole Lauroxil，结构式如下：
Figure DEST_PATH_IMAGE001
2015年10月，美国FDA批准Alkerme公司的月桂酰阿立哌唑（aripiprazole lauroxil,Aristada）缓释注射剂用于治疗精神分裂症成年患者。
发明内容
月桂酰阿立哌唑是2015年10月FDA批准上市的一种新型阿立哌唑 LAIs。目前各国均无制备专利报道。本发明将填补这一空白。
一种合成具有如下通式（I）的月桂酰阿立哌唑的方法：
Figure DEST_PATH_IMAGE003
将式（II）所代表的喹诺酮化合物：
其中X代表卤原子、芳磺酰氧基，与式（III）所代表的的哌嗪化合物和/或其盐在有机试剂中，并在有无机碱的情况下反应。
Figure DEST_PATH_IMAGE007
所用到的有机试剂为DMF、水，所述无机碱化合物是碱金属氢氧化物、碱金属碳酸盐或碱金属，所述的无机碱用量为化合物II的0.5-5倍摩尔量，应温度为0—120℃，优选80—105℃，所述的化合物II结构中的X是氯原子、溴原子，所述的化合物II结构中的X是对甲苯磺酰氧基，所述的化合物III为1-（2,3-二氯苯基）哌嗪和/或其盐。
本发明所用的试剂和原料均市售可得。
本发明的积极进步效果在于提供了一种月桂酰阿立哌唑的制备方法，目前没有报道。
具体实施方式
下面用实施例来进一步说明本发明，但本发明并不受其限制。
实施例1：
将7-[（4卤丁基）-2-氧-3,4-二氢喹啉酮-1（2H）-基]甲基十二烷酸酯50g和1-（2,3-二氯苯基）哌嗪盐酸盐30g溶于300mL DMF中，加入35g碳酸钠，搅拌加热至100℃，反应8小时，得到月桂酰阿立哌唑粗品，经过简单的提纯步骤得到高纯度的月桂酰阿立哌唑，收率81.3%，纯度99.83%。
实施例2：
将7-[（4卤丁基）-2-氧-3,4-二氢喹啉酮-1（2H）-基]甲基十二烷酸酯50g和1-（2,3-二氯苯基）哌嗪盐酸盐30g溶于450mL水中，加入18g氢氧化钠，搅拌加热至95℃，反应14小时，得到月桂酰阿立哌唑粗品，经过简单的提纯步骤得到高纯度的月桂酰阿立哌唑，收率86.4%，纯度99.66%。

Claims (8)

1.一种合成具有如下通式（I）的月桂酰阿立哌唑的方法：
Figure 590451DEST_PATH_IMAGE001
将式（II）所代表的喹诺酮化合物：
Figure 701407DEST_PATH_IMAGE002
其中X代表卤原子、芳磺酰氧基，与式（III）所代表的的哌嗪化合物和/或其盐在有机试剂中，并在有无机碱的情况下反应，
Figure 694771DEST_PATH_IMAGE003
。
2.根据权利要求1所述的制备方法，其中所用到的有机试剂为：DMF、水。
3.根据权利要求1所述的制备方法，其中所述方法仅使用一种无机碱，且所述无机碱化合物是碱金属氢氧化物、碱金属碳酸盐或碱金属。
4.根据权利要求1所述的制备方法，其中所述的无机碱用量为化合物II的0.5-5倍摩尔量。
5.根据权利要求1所述的制备方法，其反应温度为0—120℃，优选80—105℃。
6.根据权利要求1所述的制备方法，其中所述的化合物II结构中的X是氯原子、溴原子。
7.根据权利要求1所述的制备方法，其中所述的化合物II结构中的X是对甲苯磺酰氧基。
8.根据权利要求1所述的制备方法，其中所述的化合物III为1-（2,3-二氯苯基）哌嗪和/或其盐。
CN201810863547.2A 2018-08-01 2018-08-01 一种月桂酰阿立哌唑的制备方法 Pending CN110790704A (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151711A1 (en) * 2009-06-25 2010-12-29 Alkermes, Inc. Prodrugs of nh-acidic compounds
CN107628999A (zh) * 2017-10-25 2018-01-26 苏州华健瑞达医药技术有限公司 阿立哌唑十二烷酸酯的制备方法
WO2018104953A1 (en) * 2016-12-07 2018-06-14 Msn Laboratories Private Limited, R&D Center Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate
WO2018109775A1 (en) * 2016-12-14 2018-06-21 Neuland Pharma Research Private Limited Improved process for the preparation of aripiprazole lauroxil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151711A1 (en) * 2009-06-25 2010-12-29 Alkermes, Inc. Prodrugs of nh-acidic compounds
WO2018104953A1 (en) * 2016-12-07 2018-06-14 Msn Laboratories Private Limited, R&D Center Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate
WO2018109775A1 (en) * 2016-12-14 2018-06-21 Neuland Pharma Research Private Limited Improved process for the preparation of aripiprazole lauroxil
CN107628999A (zh) * 2017-10-25 2018-01-26 苏州华健瑞达医药技术有限公司 阿立哌唑十二烷酸酯的制备方法

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Application publication date: 20200214