WO2020215835A1 - 氟哌啶醇的纯化方法 - Google Patents

氟哌啶醇的纯化方法 Download PDF

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WO2020215835A1
WO2020215835A1 PCT/CN2020/071676 CN2020071676W WO2020215835A1 WO 2020215835 A1 WO2020215835 A1 WO 2020215835A1 CN 2020071676 W CN2020071676 W CN 2020071676W WO 2020215835 A1 WO2020215835 A1 WO 2020215835A1
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Prior art keywords
haloperidol
purifying
impurities
dmso
dmso solution
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PCT/CN2020/071676
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English (en)
French (fr)
Inventor
陈小林
杨易可
占娅锋
高鹏飞
孙晔
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上海旭东海普药业有限公司
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Priority to CN202080025740.4A priority Critical patent/CN113710655B/zh
Publication of WO2020215835A1 publication Critical patent/WO2020215835A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4

Definitions

  • the invention relates to a method for preparing butyrylbenzene compounds, in particular to a method for purifying haloperidol, which improves the purity of the product.
  • Haloperidol is acute and chronic schizophrenia and mania. Intramuscular injection of this product can quickly control excitement, agitation, hostility and aggressive behavior, and can also be used for brain organic mental disorders and senile mental disorders.
  • the second step reaction of this route is easy to produce multiple impurities, especially dimer impurities are difficult to remove, and it is impossible to obtain active drug molecules with qualified purity, as shown in the following formula II:
  • the common refining method is to use an organic solvent to dissolve and then crystallize to remove the impurities.
  • the purpose of the present invention is to provide a method for purifying haloperidol, which can remove dimerization impurities generated in the haloperidol synthesis process, improve product purity, and prepare active drug molecules with qualified purity.
  • a method for purifying haloperidol including:
  • the obtained crude haloperidol is dissolved in a hot DMSO solution (such as above 50°C), and the dimerization impurities insoluble in DMSO are filtered out to obtain haloperidol with a qualified content of dimerization impurities.
  • a hot DMSO solution such as above 50°C
  • Another method of purification of haloperidol includes:
  • the temperature of the DMSO solution is preferably 80°C ⁇ 0.5°C.
  • the obtained crude haloperidol is added to the hot DMSO solution to realize the efficient removal of the dimerization impurities generated in the synthesis, so that the obtained haloperidol dimerization impurities
  • the content is less than 0.05w/w%.
  • the purification method provided by the present invention is safe and efficient, and the product yield is high without changing the original purification process.
  • the starting material III (20.1g), intermediate (57.0g), potassium iodide (0.80g), sodium carbonate (20.0g) and methyl isobutyl ketone (600mL) were added to the reaction flask, heated and stirred at 130°C for 6 Hour (HPLC detection of starting material III ⁇ 5.0%), cool to 50°C, add water (200mL) and stir for 0.5h, separate the organic layer, the organic layer will continue to fall to 10°C ⁇ 20°C for crystallization, filter, filter cake with a small amount of forma Isobutyl ketone was washed and dried by blowing at 55°C to obtain 30.0 g of product with a yield of 84.1%.
  • the refined solvent ethanol/water
  • the purity of the crude haloperidol is 89.37%, 99.12% after purification
  • the dimerization impurity content is about 0.4w/w%, indicating that the removal of dimerization impurities is not significant, and other impurities Obviously removed.
  • the refining solvent isopropanol. After isopropanol is heated and dissolved, the yield is 86.7%, and the dimerization impurity content is about 0.3w/w%, and the removal effect is not significant.
  • the yield of ethanol is 82.39%, and the content of dimerization impurities is about 0.35 w/w%, and the removal effect is not significant.
  • the refined solvent DMSO
  • the total yield 86%
  • the dimerization impurity content 0.04 w/w%, and the removal effect is significantly improved.

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

Abstract

一种氟哌啶醇的纯化方法，先将制得的氟哌啶醇粗品溶于热的DMSO溶液中，过滤除掉不溶于DMSO的二聚杂质，即得二聚杂质含量合格的氟哌啶醇。本发明提供的氟哌啶醇的纯化方法，将制得的氟哌啶醇粗品加入热的DMSO溶液中实现了将合成中产生的二聚杂质高效除去，使得所得氟哌啶醇的二聚杂质含量低于0.05w/w％。。

Description

氟哌啶醇的纯化方法 技术领域
本发明涉及一种制取丁酰苯类化合物的方法，尤其涉及一种氟哌啶醇的纯化方法，提高产物的纯度。
背景技术
氟哌啶醇急、慢性各型精神分裂症、躁狂症。肌内注射本品可迅速控制兴奋躁动、敌对情绪和攻击行为，也可用于脑器质性精神障碍和老年性精神障碍。
合成工艺路线如下式Ⅰ所示：
Figure PCTCN2020071676-appb-000001
此路线第二步反应易生产多个杂质，尤其是二聚杂质难以去除，无法取得纯度合格的活性药物分子，如下式Ⅱ所示：
Figure PCTCN2020071676-appb-000002
常用的精制手段为使用有机溶剂溶解后再结晶的方式去除该杂质。
发明内容
本发明的目的在于提供一种氟哌啶醇的纯化方法，去除在氟哌啶醇合成工艺中产生的二聚杂质，提高产物纯度，制取纯度合格的活性药物分子。
一种氟哌啶醇的纯化方法，包括：
先将制得的氟哌啶醇粗品溶于热的DMSO溶液(如：50℃以上)中，过滤除掉不溶于DMSO的二聚杂质，即得二聚杂质含量合格的氟哌啶醇。
另一种氟哌啶醇的纯化方法，包括：
先将制得的氟哌啶醇粗品溶于70℃～90℃的DMSO溶液中，使得二聚杂质从DMSO溶液中析出后，以过滤方式除掉不溶于DMSO的二聚杂质；
接着，待滤液冷却后，取得析出的氟哌啶醇；
之后，向析出的氟哌啶醇中加入无水乙醇，均质(如：打浆)以除去DMSO溶剂残留，即得二聚杂质含量低于0.05w/w％的氟哌啶醇。
本发明提供的氟哌啶醇的纯化方法，优先选择DMSO溶液的温度为80℃±0.5℃。
本发明技术方案实现的有益效果：
本发明提供的氟哌啶醇的纯化方法，将制得的氟哌啶醇粗品加入热的DMSO溶液中实现了将合成中产生的二聚杂质高效除去，使得所得氟哌啶醇的二聚杂质含量低于0.05w/w％。
与现有已公开的技术相比，本发明提供的纯化方法，安全高效，产品收率高，无需改变原有纯化工艺。
具体实施方式
以下详细描述本发明的技术方案。本发明实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
实施例1制取氟哌啶醇粗品(170826批次，二聚杂质含量：0.38w/w％)
Figure PCTCN2020071676-appb-000003
500mL反应瓶中加入起始原料III(10.01g)，中间体(28.40g)，碳酸钠(10.01g)，碘化钾(3.92g)和甲基异丁基甲酮(200mL)，升温至130℃，加热搅拌，反应6小时(HPLC检测起始原料III＜5.0％)，降温至50℃，加水(100mL)搅拌0.5h，分离有机层，有机层继续降至10-20℃析晶，过滤，滤饼用少量甲基异丁基甲酮洗涤，55℃鼓风干燥得产品14.7g，收率82.7％。
实施例2制取氟哌啶醇粗品(170808批次，二聚杂质含量：0.57w/w％)
反应瓶中加入起始原料III(20.1g)，中间体(57.0g)，碘化钾(0.80g)，碳酸钠(20.0g)和甲基异丁基甲酮(600mL)，加热升温搅拌，130℃反应6小时(HPLC检测起始原料III＜5.0％)，降温至50℃，加水(200mL)搅拌0.5h，分离有机层，有机层继续降至10℃～20℃析 晶，过滤，滤饼用少量甲基异丁基甲酮洗涤，55℃鼓风干燥得产品30.0g，收率84.1％。
实施例3氟哌啶醇粗品的精制
100mL反应瓶中加入粗品1.0g(批次170821-2)，无水乙醇10mL，搅拌加热至70℃，溶清后，滴加水2mL，体系浑浊，降温至10℃～20℃，过滤，55℃鼓风干燥得0.80g，收率80.0％。
本实施例中，精制溶剂：乙醇/水，粗品的氟哌啶醇纯度为89.37％，纯化后99.12％，二聚杂质含量约为0.4w/w％，表明二聚杂质去除不显著，其它杂质已明显去除。
实施例4氟哌啶醇粗品的精制
100mL反应瓶中加入粗品3.0g(批次170901-2)，异丙醇90mL，搅拌加热至90℃，溶清后热过滤，滤液降温析晶，降至5℃～10℃后，搅拌1小时～2小时，过滤，滤饼55℃鼓风干燥得产品2.60g，收率86.7％。
本实施例中，精制溶剂：异丙醇，异丙醇加热溶清后，收率86.7％，二聚杂质含量约为0.3w/w％，去除效果不显著。
实施例5氟哌啶醇粗品的精制
500mL反应瓶中加入无水乙醇400mL，搅拌，加热至70℃，加入粗品20.05g(批次170928-1)，溶清后，热过滤，降温析晶，10℃～20℃搅拌1小时～2小时，过滤，滤饼用少量无水乙醇洗涤，55℃鼓风干燥的16.52g，收率82.39％。
本实施例中，乙醇，收率82.39％，二聚杂质含量约为0.35w/w％，去除效果不显著。
实施例6氟哌啶醇粗品的精制
2L反应瓶中加入50.00g粗品(批次171018-1)，300mL DMSO加热至80℃～90℃，搅拌2h，热过滤，降至室温，10℃～20℃下继续搅拌析晶1小时～2小时，过滤，得滤饼(滤饼不干燥直接进行下一步)，滤饼用无水乙醇(500mL)回流打浆2小时，降温至10℃～20℃，过滤，滤饼用少量无水乙醇洗涤，滤饼在55℃鼓风干燥8h，得产品43.00g，收率86.0％
本实施例中，精制溶剂：DMSO，总收率：86％,二聚杂质含量0.04w/w％，去除效果显著提高。

Claims (7)

  1. 一种氟哌啶醇的纯化方法，其特征在于包括如下步骤：
    先将制得的氟哌啶醇粗品溶于热的DMSO溶液中，过滤除掉不溶于DMSO的二聚杂质，即得二聚杂质含量合格的氟哌啶醇。
  2. 根据权利要求1所述的氟哌啶醇的纯化方法，其特征在于所述的DMSO溶液温度大于50℃。
  3. 根据权利要求1所述的氟哌啶醇的纯化方法，其特征在于所述的DMSO溶液温度70℃～90℃。
  4. 根据权利要求1所述的氟哌啶醇的纯化方法，其特征在于所述的DMSO溶液温度80℃±0.5℃。
  5. 根据权利要求1所述的氟哌啶醇的纯化方法，其特征在于所述的二聚杂质含量合格的氟哌啶醇，其中二聚杂质含量低于0.05w/w％。
  6. 一种氟哌啶醇的纯化方法，其特征在于包括如下步骤：
    先将制得的氟哌啶醇粗品溶于70℃～90℃的DMSO溶液中，使得二聚杂质从DMSO溶液中析出后，以过滤方式除掉不溶于DMSO的二聚杂质；
    接着，待滤液冷却后，取得析出的氟哌啶醇；
    之后，向析出的氟哌啶醇中加入无水乙醇，均质以除去DMSO溶剂残留，即得二聚杂质含量低于0.05w/w％的氟哌啶醇。
  7. 根据权利要求6所述的氟哌啶醇的纯化方法，其特征在于所述的DMSO溶液温度80℃±0.5℃。
PCT/CN2020/071676 2019-04-22 2020-01-13 氟哌啶醇的纯化方法 WO2020215835A1 (zh)

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CN109970624B (zh) * 2019-04-22 2020-05-22 上海旭东海普药业有限公司 氟哌啶醇的纯化方法
CN112538042A (zh) * 2020-12-15 2021-03-23 湖南洞庭药业股份有限公司 一种氟哌啶醇的制备方法

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