WO2020216146A1 - 一种左乙拉西坦中间体的制备方法 - Google Patents

一种左乙拉西坦中间体的制备方法 Download PDF

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WO2020216146A1
WO2020216146A1 PCT/CN2020/085370 CN2020085370W WO2020216146A1 WO 2020216146 A1 WO2020216146 A1 WO 2020216146A1 CN 2020085370 W CN2020085370 W CN 2020085370W WO 2020216146 A1 WO2020216146 A1 WO 2020216146A1
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ethyl
oxo
acetic acid
pyrrolidine acetic
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PCT/CN2020/085370
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刘冰欣
龚玉龙
朱元勋
颜峰峰
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浙江华海药业股份有限公司
浙江华海致诚药业有限公司
浙江华海天诚药业有限公司
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Priority to CN202080008317.3A priority Critical patent/CN113272275B/zh
Priority to US17/600,535 priority patent/US20220162165A1/en
Priority to EP20795993.3A priority patent/EP3960732A4/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • the invention relates to a method for preparing a levetiracetam intermediate, which belongs to the field of medicine and chemical industry.
  • Levetiracetam (Levetiracetam, trade name Keppra) is a new type of antiepileptic drug developed by the Belgian company UCB. It is an acetylpyrrolidine compound whose chemical name is (S)- ⁇ -ethyl -2-oxo-1-acetamide pyrrolidine, the structure is as follows:
  • CN85105301A reports a method for synthesizing levetiracetam, including splitting ( ⁇ )- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid (II) to obtain (S)- ⁇ -ethyl-2 -Oxo-1-pyrrolidine acetic acid (III), then esterification and ammonolysis to obtain crude levetiracetam, and finally refining to obtain levetiracetam.
  • the specific synthesis route is as follows:
  • the compound represented by formula II ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid is its key intermediate.
  • compound III There are a small amount of compound III and a large amount of isomer (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid in the mother liquor of the resolution reaction, as shown in formula V.
  • Patent CN101333180 reported a method for recovering ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid by high temperature racemization of the by-product (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid.
  • the purpose of the present invention is to provide a method for obtaining high-quality (RS)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid (i.e. racemic ⁇ -ethyl-2-oxo-1-pyrrole
  • the method of alkanoacetic acid includes the following steps:
  • the mixture of (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid and (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid in step (a) can be derived from (RS)- ⁇ -Ethyl-2-oxo-1-pyrrolidine acetic acid is used to resolve the evaporative dry matter of the mother liquor.
  • the strong base is selected from sodium hydroxide or potassium hydroxide; the mass percentage concentration of the strong base solution ranges from 25% to 40%; the amount of the strong base is (R)- ⁇ -ethyl
  • the total molar amount of the mixture of -2-oxo-1-pyrrolidine acetic acid and (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid is 1 to 3 times.
  • the amount of water used in step (b) is (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid and (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid 1.5 to 5 times the total mass of the mixture.
  • the decolorization time in step (c) is preferably 0.5 to 1.5 hours.
  • the innovation of the present invention lies in: by adjusting the pH value to an appropriate range at an appropriate temperature through step (b), (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid is produced in the process of strong base racemization
  • the unknown impurity can be precipitated in the system (the above unknown impurity does not show a peak in the whole process of HPLC analysis.
  • step (c) The decolorization process of step (c); through the above operation, the quality and appearance of the obtained racemic recovered intermediate (RS)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetic acid is very good, and it is also not It affects the product yield, thus reducing the risk of introducing unknown impurities into the finished product of Levetiracetam, and has good practical value.
  • FIG. 1 is a photograph of the appearance of a sample of a comparative example and Example 1 of the present application; the left image is the appearance of the sample of the comparative example, and the right image is the appearance of the sample of Example 1 of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)

Abstract

本申请提供了一种通过消旋回收获得高质量的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，本申请提供的方法可以显著提高消旋回收产品(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的质量和外观，且对产品收率无影响。

Description

一种左乙拉西坦中间体的制备方法
本申请要求于2019年4月23日提交中国专利局、申请号为201910328462.9发明名称为“一种左乙拉西坦中间体的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种左乙拉西坦中间体的制备方法，属于医药化工领域。
背景技术
左乙拉西坦(Levetiracetam，商品名为Keppra)是由比利时公司UCB研制的一种新型的抗癫痫药物，它是一种乙酰吡咯烷类化合物，其化学名称为(S)-α-乙基-2-氧合-1-乙酰胺吡咯烷，结构如下所示：
Figure PCTCN2020085370-appb-000001
CN85105301A报道了一种左乙拉西坦的合成方法，包括拆分(±)-α-乙基-2-氧代-1-吡咯烷乙酸(II)得到(S)-α-乙基-2-氧代-1-吡咯烷乙酸(III)，然后经酯化、氨解得到左乙拉西坦粗品，最后精制得到左乙拉西坦。具体合成路线如下所示：
Figure PCTCN2020085370-appb-000002
其中式II所示的化合物α-乙基-2-氧代-1-吡咯烷乙酸为其关键中间体。拆分反应母液中存在少量的化合物III以及大量的异构体(R)-α-乙基-2-氧代-1-吡咯烷乙酸，如式V所示。专利CN101333180报道了将副产物(R)-α-乙基-2-氧代-1-吡咯烷乙酸经高温消旋回收α-乙基-2-氧代-1-吡咯烷乙酸的方法。
Figure PCTCN2020085370-appb-000003
但由于专利CN101333180报道的回收方法为强碱下高温消旋，会产生较多的杂质，对后续生产左乙拉西坦质量产生影响。
发明内容
本发明的目的是提供一种获得高质量的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸(即外消旋的α-乙基-2-氧代-1-吡咯烷乙酸)的方法，包括以下步骤：
(a)将包含(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物加入到强碱水溶液中，升温至80～95℃，保温搅拌8～12小时；
(b)加适量水稀释并降温至40～60℃，滴加盐酸调节pH至6.0～8.0，
(c)继续保持40～60℃下，加入活性炭或硅藻土吸附脱色一段时间后，趁热过滤；
(d)滤液升温并控制在70～90℃下滴加盐酸调节pH至1.0～2.5；
(e)降温至0～10℃，过滤，烘干得到(RS)-α-乙基-2-氧代-1-吡咯烷乙酸。
步骤(a)所述(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物可以来源于(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液的蒸干物。
步骤(a)所述强碱选自：氢氧化钠或氢氧化钾；所述强碱溶液质量百分比浓度范围为25％～40％；所述强碱的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物总摩尔量的1～3倍。
步骤(b)所述水的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α- 乙基-2-氧代-1-吡咯烷乙酸的混合物总质量的1.5～5倍。
步骤(c)中脱色时间优选为0.5～1.5小时。
本发明的创新点在于：通过步骤(b)在适宜温度下调节pH值至适当范围，(R)-α-乙基-2-氧代-1-吡咯烷乙酸在强碱消旋过程中产生的未知杂质可以在体系中析出(上述未知杂质在HPLC分析中全程不出峰，此时如果进行过滤，滤纸会出现大量黑色固体，但是滤液仍为黄色)，在步骤(b)的温度下继续步骤(c)的脱色工序；通过以上操作，所获得的消旋回收的中间体(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的质量和外观非常好，同时也未影响产品收率，因此降低了未知杂质引入到左乙拉西坦成品的风险，具有很好的实用价值。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为对比实施例及本申请实施例一的样品外观照片；其中，左图为对比实施例的样品外观，右图为本发明实施例一的样品外观。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
对比实施例：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入23g 30％液碱(氢氧化钠)调节pH至12～14，于80～95℃下搅拌反应8～10小时，加入100g水稀释并降温至60℃后加入盐酸调节pH至1.5，降温至5℃析晶得到回收(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.6g，纯度为99.4％。产品颜色偏黄，参见附图一的左图。
实施例一：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入45g 25％液碱(氢氧化钠)调节pH至13～14，于85～90℃下保温搅拌反应8～10小时，加入100g饮用水稀释并降温至60℃后加入盐酸调节pH至7.0，体系中出现大量黑褐色悬浮杂质，加入0.5g活性炭保温搅拌0.5h后抽滤，滤液升温至70～90℃并控制在该温度下继续用盐酸调节pH至1.5，降温至0～10℃析晶得到回收的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.6g，纯度为99.9％。产品颜色为白色。参见附图一的右图。
实施例二：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入30g 30％液碱(氢氧化钠)调节pH至＝12～14，于85～95℃下搅拌反应8～10小时，加入100g饮用水稀释并降温至60℃后加入盐酸调节pH至6.0，体系中出现大量黑褐色悬浮杂质，加入0.5g活性炭保温搅拌1.5h后抽滤，滤液升温至70～90℃并控制在该温度下继续用盐酸调节pH至2.0，降温至5℃析晶得到回收的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.4g，纯度为99.9％。产品为白色。
实施例三：
取(RS)-α-乙基-2-氧代-1-吡咯烷乙酸拆分母液旋干物20g于四口瓶中，加入16g 35％液碱(氢氧化钠)调节pH至12～14，于85～90℃下搅拌反应8～10小时，加入100g饮用水稀释并降温至60℃后加入盐酸调节pH至6.0，体系中出现大量黑褐色悬浮杂质，加入0.5g药用硅藻土保温搅拌1.0h后抽滤，滤液升温至70～90℃并控制在该温度下继续用盐酸调节pH至1.5，降温至5℃析晶得到回收的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸，烘干称重得19.5g，纯度为99.7％。产品颜色为白色。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (6)

  1. 一种制备(RS)-α-乙基-2-氧代-1-吡咯烷乙酸的方法，包括以下步骤：
    (a)将包含(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸的混合物加入到强碱水溶液中，升温至80～95℃，保温搅拌8～12小时；
    (b)加适量水稀释并降温至40～60℃，滴加盐酸调节pH至6.0～8.0；
    (c)继续保持40～60℃下，加入活性炭或硅藻土吸附脱色一段时间后，趁热过滤；
    (d)滤液升温并控制在70～90℃下滴加盐酸调节pH至1.0～2.5；
    (e)降温至0～10℃，过滤，烘干得到(RS)-α-乙基-2-氧代-1-吡咯烷乙酸。
  2. 根据权利要求1所述的方法，其中步骤(a)中所述强碱选自氢氧化钠或氢氧化钾。
  3. 根据权利要求1所述的方法，其中步骤(a)中所述强碱水溶液的质量百分比浓度范围25％～40％。
  4. 根据权利要求1所述的方法，其中步骤(a)中所述强碱的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸混合物总摩尔量的1～3倍。
  5. 根据权利要求1所述的方法，其中步骤(b)中水的用量为(R)-α-乙基-2-氧代-1-吡咯烷乙酸和(S)-α-乙基-2-氧代-1-吡咯烷乙酸混合物总质量的1.5～5倍。
  6. 根据权利要求1所述的方法，其中步骤(c)中脱色时间为0.5～1.5小时。
PCT/CN2020/085370 2019-04-23 2020-04-17 一种左乙拉西坦中间体的制备方法 WO2020216146A1 (zh)

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US11384050B1 (en) 2021-02-03 2022-07-12 Vitaworks Ip, Llc Method for preparing levetiracetam and intermediates thereof

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CN110003074A (zh) * 2019-04-23 2019-07-12 浙江华海药业股份有限公司 一种左乙拉西坦中间体的制备方法
CN114702426A (zh) * 2022-05-24 2022-07-05 雅本化学股份有限公司 一种左乙拉西坦中间体的合成方法

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