左乙拉西坦酸 | 103833-72-3

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 左乙拉西坦酸
• 中文别名: (R)-2-(2-氧代-1-吡咯烷基)丁酸；(R)-alpha-乙基-2-氧代-1-吡咯烷乙酸；羧酸左乙拉西坦
• 英文名称: (R)-2-pyrrolidone-N-butyric acid
• 英文别名: (R)-2-(2-oxopyrrolidin-1-yl)butyric acid；2-(2-oxopyrrolidin-1-yl)butanoic acid；(R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid；2-(2-Oxopyrrolidin-1-yl)butanoic acid, (2R)-；(2R)-2-(2-oxopyrrolidin-1-yl)butanoic acid
• CAS: 103833-72-3
• 化学式: C₈H₁₃NO₃
• 分子量: 171.196
• InChiKey: IODGAONBTQRGGG-ZCFIWIBFSA-N

物化性质

• 熔点：
  124-126 °C
• 沸点：
  371 °C
• 密度：
  1.227
• 闪点：
  178 °C
• 溶解度：
  可溶于丙酮（轻微，超声处理）、氯仿（轻微）、甲醇（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

左乙拉西坦酸是制备左乙拉西坦的中间体。左乙拉西坦是由比利时UCB（优时比）公司研发的一种新型抗癫痫药物，于2000年4月获FDA批准在美国和欧盟上市，主要用于治疗局限性及继发性全身性癫痫。

反应信息

• 作为反应物：
  描述：

  左乙拉西坦酸 在 氯甲酸乙酯 、 三乙胺 、 ammonium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 16.5h， 以63%的产率得到(R)-2-(2-氧代吡咯烷-1-基)丁酰胺
  参考文献：
  名称：

  A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

  摘要：

  The synthesis of levetiracetarn and its enantiomer by deracernization of (+/-)-2-bromobutyric acid using either (S)- or (R)N-phenylpantolactarn as chiral auxiliaries, followed by S-N(2) substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2005.10.014
• 作为产物：
  描述：

  alpha-乙基-2-氧代-1-吡咯烷乙酸 在 lithium hydroxide 、 双氧水 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 23.33h， 生成 左乙拉西坦酸
  参考文献：
  名称：

  A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

  摘要：

  The synthesis of levetiracetarn and its enantiomer by deracernization of (+/-)-2-bromobutyric acid using either (S)- or (R)N-phenylpantolactarn as chiral auxiliaries, followed by S-N(2) substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2005.10.014

文献信息

• Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies
  作者：Irene Sola、Ester Aso、Daniela Frattini、Irene López-González、Alba Espargaró、Raimon Sabaté、Ornella Di Pietro、F. Javier Luque、M. Victòria Clos、Isidro Ferrer、Diego Muñoz-Torrero

  DOI：10.1021/acs.jmedchem.5b00624

  日期：2015.8.13

  cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer’s disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of

  我们已经合成了一系列由七亚甲基连接的左乙拉西坦-胡派林和左乙拉西坦-（6-氯）他克林杂种，以击中淀粉样蛋白，tau蛋白和胆碱能病理学以及β-淀粉样蛋白（Aβ）诱导的癫痫样活性，其中一些机制最终导致阿尔茨海默氏病患者的认知功能障碍。这些杂合体在体外是人乙酰胆碱酯酶和丁酰胆碱酯酶的有效抑制剂，在简单的淀粉样蛋白大肠杆菌模型中是中等有效的Aβ42和tau抗聚集剂。腹膜内注射给C57BL6J小鼠后，这些化合物的脑内乙酰胆碱酯酶抑制活性的离体测定证明了它们进入大脑的能力。左乙拉西坦-胡派林杂种10用5 mg / kg剂量治疗4周后，可显着降低APP / PS1小鼠的癫痫发作，皮质淀粉样蛋白负荷和神经炎症的发生率。此外，杂种10从认知缺陷中拯救了转基因小鼠，从而成为一种有趣的疾病改良抗阿尔茨海默氏症候选药物。
• Scalable Flow Electrochemical Alcohol Oxidation: Maintaining High Stereochemical Fidelity in the Synthesis of Levetiracetam
  作者：Xing Zhong、Md Asmaul Hoque、Matthew D. Graaf、Kaid C. Harper、Fei Wang、J. David Genders、Shannon S. Stahl

  DOI：10.1021/acs.oprd.1c00036

  日期：2021.12.17

  is the retention of high enantiomeric purity as the oxidation of the primary alcohol to the carboxylic acid proceeds via an epimerizable aldehyde intermediate. Here, three different reactor configurations are compared: undivided batch, undivided flow, and divided flow cells. The divided flow cell accesses the highest rate, throughput, and enantiomeric fidelity among the three configurations. This approach

  已开发出一种电化学流程，用于合成癫痫药物左乙拉西坦中的醇氧化步骤。该过程中的一个关键指标是保持高对映体纯度，因为伯醇氧化为羧酸是通过可差向异构的醛中间体进行的。在这里，比较了三种不同的反应器配置：未分开的批次、未分开的流动和分开的流动池。分开的流通池在三种配置中具有最高的速率、通量和对映体保真度。这种方法在 200 克规模的工艺中得到展示，该工艺保留了 ≥ 97% 的对映体纯度，并突出了流动电解的独特优势。
• PROCESS FOR THE PREPARATION OF LEVETIRACETAM
  申请人：FORCATO Massimiliano

  公开号：US20100076204A1

  公开（公告）日：2010-03-25

  The present invention relates to a process for the preparation of levetiracetam and, more particularly, to an improved process for the preparation of levetiracetam characterized by a crystallization-induced dynamic resolution of a diastereoisomeric mixture of an (±)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide derivative.

  本发明涉及一种制备左乙拉西坦的方法，更具体地说，涉及一种通过晶体化诱导动态分辨(±)-α-乙基-2-氧代-1-吡咯烷乙酰胺衍生物的对映异构体混合物的改进制备左乙拉西坦的方法。
• Process For The Preparation Of (S)-Alpha-Ethyl-2-Oxo-1-Pyrrolidineacetamide And (R)- Alpha-Ethyl-2-Oxo-Pyrrolidineacetamide
  申请人：Li Yuan Qiang

  公开号：US20090069575A1

  公开（公告）日：2009-03-12

  A process provided for the preparation of the (S)— and (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide of formula:(1) from (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid of formula:(2) comprising: i) combining the (RS)-2 with a chiral base (resolving agent) in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)— or (R)-2 and chiral base; ii) regenerating (S)— or (R)-2 from the crystallized diastereomeric salt by treating with a suitable acid or acidic ion-exchange resin; iii) optionally regenerating (R)— or (S)-2 or their mixture (predominantly one enantiomer) from the crystallization mother liquor by treating with a suitable acid or acidic ion-exchange resin; iv) optionally epimerizing (RS)-2 by treating (R)— or (S)-2 or their mixture (predominantly one enantiomer) of step iii with an acid anhydride; V) optionally converting (RS)-2 of step iv into enantiomerically enriched (S)— or (R)-2 through steps i and ii; vi) formation of the mixed anhydride by reacting (R)— or (S)-2 with an alkyl or aryl sulfonyl halogen compound RSO2X in the presence of a suitable base; and vii) reacting the mixed anhydride with ammonia; wherein R represents C 1 to C 15 alkyl or aryl groups such as methyl, ethyl, p-toluenyl, 2,4,6-trimethylbenzyl, 2,4,6-trichloribenzyl, and X represents a halogen atom such as F, Cl and Br atoms.

  提供了一种从式（2）的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸制备式（1）的(S)-和(R)-α-乙基-2-氧代-1-吡咯烷乙酰胺的方法，包括：i）将(RS)-2与手性碱（分离剂）在分离溶剂中混合，并从所述混合物中结晶出(S)-或(R)-2和手性碱的非对映异构盐；ii）通过用适当的酸或酸性离子交换树脂处理结晶得到的非对映异构盐来再生(S)-或(R)-2；iii）通过用适当的酸或酸性离子交换树脂处理结晶母液中的(R)-或(S)-2或它们的混合物（主要是一种对映体）来可选地再生(R)-或(S)-2或它们的混合物（主要是一种对映体）；iv）通过用酸酐处理步骤iii中的(R)-或(S)-2或它们的混合物（主要是一种对映体）可选地使(RS)-2外消旋化；v）通过步骤i和ii将步骤iv中的(RS)-2转化为对映富集的(S)-或(R)-2；vi）通过在适当的碱存在下，将(R)-或(S)-2与烷基或芳基磺酰卤化物RSO2X反应形成混合酸酐；vii）将混合酸酐与氨反应；其中R代表C1到C15的烷基或芳基基团，例如甲基、乙基、对甲苯基、2,4,6-三甲基苯基、2,4,6-三氯苯基，X代表卤素原子，例如F、Cl和Br原子。
• Process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (R)-alpha-ethyl-2-oxo-pyrrolidineacetamide
  申请人：Apotex Pharmachem Inc.

  公开号：US07902380B2

  公开（公告）日：2011-03-08

  A process provided for the preparation of the (S)- and (R)- alpha- ethyl-2-oxo-1-pyrrolidineacetamide of formula:(1) from (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid of formula:(2) comprising: i) combining the (RS)-2 with a chiral base (resolving agent) in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-2 and chiral base; ii) regenerating (S)- or (R)-2 from the crystallized diastereomeric salt by treating with a suitable acid or acidic ion-exchange resin; iii) optionally regenerating (R)- or (S)-2 or their mixture (predominantly one enantiomer) from the crystallization mother liquor by treating with a suitable acid or acidic ion-exchange resin; iv) optionally epimerizing (RS)-2 by treating (R)- or (S)-2 or their mixture (predominantly one enantiomer) of step iii with an acid anhydride; V) optionally converting (RS)-2 of step iv into enantiomerically enriched (S)- or (R)-2 through steps i and ii; vi) formation of the mixed anhydride by reacting (R)- or (S)-2 with an alkyl or aryl sulfonyl halogen compound RSO2X in the presence of a suitable base; and vii) reacting the mixed anhydride with ammonia; wherein R represents C 1 to C 15 alkyl or aryl groups such as methyl, ethyl, p-toluenyl, 2,4,6-trimethylbenzyl, 2,4,6-trichloribenzyl, and X represents a halogen atom such as F, Cl and Br atoms.

  提供了一种从式(2)的(RS)-α-乙基-2-氧代-1-吡咯烷乙酸制备式(1)的(S)-和(R)-α-乙基-2-氧代-1-吡咯乙酰胺的方法，包括：i）在分辨剂溶剂中将(RS)-2与手性碱（分辨剂）结合，并从所述混合物中结晶出(S)-或(R)-2和手性碱的对映异构盐；ii）通过使用适当的酸或酸性离子交换树脂处理结晶出的对映异构盐来再生(S)-或(R)-2；iii）通过使用适当的酸或酸性离子交换树脂，可选地再生(S)-或(R)-2或它们的混合物（主要是一种对映体）从结晶母液中；iv）通过使用酸酐处理步骤iii中的(R)-或(S)-2或它们的混合物（主要是一种对映体）可选地使(RS)-2外消旋化；v）通过步骤i和ii将步骤iv中的(RS)-2转化为对映富集的(S)-或(R)-2；vi）在适当的碱存在下，通过将(R)-或(S)-2与烷基或芳基磺酰卤化物RSO2X反应形成混合酐；vii）用氨反应混合酐；其中R代表C1到C15的烷基或芳基基团，例如甲基、乙基、对甲苯基、2,4,6-三甲基苯基、2,4,6-三氯苯基，X代表氟、氯和溴原子。