乙基2-丙基-4-戊烯酸酯 | 96107-26-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 乙基2-丙基-4-戊烯酸酯
• 英文名称: ethyl 2-n-propyl-4-pentenoate
• 英文别名: ethyl 2-propyl-4-pentenoate；ethyl 2-propylpent-4-enoate
• CAS: 96107-26-5
• 化学式: C₁₀H₁₈O₂
• 分子量: 170.252
• InChiKey: XCTMFTZXTGVJHP-UHFFFAOYSA-N

物化性质

• 沸点：
  187.9±9.0 °C(Predicted)
• 密度：
  0.884±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  12
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  乙基2-丙基-4-戊烯酸酯 在 lithium diisopropyl amide 、 N-氟苯磺酰胺 作用下， 以 四氢呋喃 、 六甲基磷酰三胺 、 正己烷 为溶剂， 反应 1.0h， 以86%的产率得到2-氟-2-丙基戊-4-烯酸乙酯
  参考文献：
  名称：

  Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

  摘要：

  It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F-2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F-2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg); and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the (alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.

  DOI：

  10.1021/tx00047a006
• 作为产物：
  描述：

  丙基丙二酸二乙酯 在 咪唑 、 sodium hydride 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 75.07h， 生成 乙基2-丙基-4-戊烯酸酯
  参考文献：
  名称：

  An improved solvent-free system for the microwave-assisted decarboxylation of malonate derivatives based on the use of imidazole

  摘要：

  A comparative study of the thermal and microwave-assisted decarboxylation of a series of mono- and disubstituted monohydrolyzed malonate derivatives has been carried out. It has been found out that in both circumstances the use of imidazole has a profound effect on the success of the reaction. In general terms the assistance of microwave irradiation accelerates the decarboxylation process significantly and, at the same time, permits the use of minored temperatures with respect to the thermal via. It has been also found that both the thermal and the microwave-assisted transformation can be developed under solvent-free conditions. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2015.09.012

文献信息

• Stereoselective Synthesis of the Diunsaturated Metabolites of Valproic Acid
  作者：Ronald D. Lee、Kelem Kassahun、Frank S. Abbott

  DOI：10.1002/jps.2600780813

  日期：1989.8

  Two diene metabolites of valproic acid (VPA), (E)-2-n-propyl-2,4-pentadienoic acid and (E)-2-(1'-propenyl)-(E)-2-pentenoic acid, were stereoselectively synthesized. Mesylate elimination in the final step to produce the unsaturation at position 2 was stereospecific for the (E)-configuration in the case of 2. Gas chromatography-mass spectroscopy and NMR were used to confirm the configuration of each

  丙戊酸（VPA）的两种二烯代谢物分别是（E）-2-n-丙基-2,4-戊二烯酸和（E）-2-（1'-丙烯基）-（E）-2-戊烯酸立体选择性地合成。在2的情况下，最后一步在位置2产生不饱和基的甲磺酸酯消除对（E）-构型是立体定向的。使用气相色谱-质谱和NMR确认每个二烯的构型，包括次要异构体，（ Z）-2-正丙基-2,4-戊二烯酸和（Z）-2-（1'-丙烯基）-（E）-2-戊烯酸。通过负化学电离GC-MS对来自VPA治疗患者血清提取物的PFB衍生物进行分析，发现二烯为四个峰，按照洗脱顺序分别对应于9、18、1和2。
• [EN] VALPROIC ACID ANALOGUES AND PHARMACEUTICAL COMPOSITIONS THEREOF<br/>[FR] ANALOGUES DE L'ACIDE VALPROIQUE ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT
  申请人：UNIV BRITISH COLUMBIA

  公开号：WO2004054957A3

  公开（公告）日：2004-09-10
• Characterization of Thiol-conjugated Metabolites of 2-Propylpent-4-enoic Acid (4-eneVPA), a Toxic Metabolite of Valproic Acid, by Electrospray Tandem Mass Spectrometry
  作者：Wei Tang、Frank S. Abbott

  DOI：10.1002/(sici)1096-9888(199608)31:8<926::aid-jms383>3.0.co;2-p

  日期：1996.8

  The hepatotoxicity of the anticonvulsant drug valproic acid (VPA) is most likely associated with the bioactivation of its metabolite 2-propylpent-4-enoic acid (4-ene VPA), which is known to induce hepatic microvesicular steatosis in rats. This paper presents an on-line liquid chromatographic/tandem mass spectrometric (LC/MS/MS) identification of new glutathione (GSH)-related conjugates of the reactive metabolites of 4-ene VPA. Bile samples collected from male Sprague-Dawley rats dosed intraperitoneally with 4-ene VPA or its [2H7]-analogue (100 mg kg-1) were injected on to an ODS column interfaced to a LC/MS/MS instrument using electrospray ionization. LC was developed such that no overlapping of peaks occurred among those metabolites which may potentially produce common fragment ions of interest. Subsequent comparison of LC retention times and MS/MS full fragment ion spectra generated for putative metabolites with that of authentic reference compounds made available by chemical synthesis confirmed the presence of the GSH, cysteinylglycine, cysteine and N-acetylcysteine (NAC) conjugates of 2-(2'-carboxypentanyl)oxirane (4,5-epoxy VPA) and (E)-2-propylpenta-2,4-dienoic acid ((E)-2,4-diene VPA), respectively. Quantitatively, the biliary thiol conjugates accounted for 5% of the dose. This observation is novel for 4-ene VPA metabolism in terms of the degradation of GSH conjugates to the corresponding mercapturic acids possibly occurring within the liver as opposed to an inter-organ process which involves the kidney. In addition, the GSH- and NAC-glucuronide di-conjugates of (E)-2,4-diene VPA were also identified as the biliary metabolites with the GSH-glucuronide di-conjugate being 10% of the corresponding mono-GSH conjugate. Taken together, these data clearly indicate that reactive metabolites of VPA can react with hepatic GSH via several different metabolic pathways and may subsequently produce depletion of GSH that leads to toxic consequences.
• An improved solvent-free system for the microwave-assisted decarboxylation of malonate derivatives based on the use of imidazole
  作者：Imanol Tellitu、Itziar Beitia、Marta Díaz、Argiñe Alonso、Isabel Moreno、Esther Domínguez

  DOI：10.1016/j.tet.2015.09.012

  日期：2015.10

  A comparative study of the thermal and microwave-assisted decarboxylation of a series of mono- and disubstituted monohydrolyzed malonate derivatives has been carried out. It has been found out that in both circumstances the use of imidazole has a profound effect on the success of the reaction. In general terms the assistance of microwave irradiation accelerates the decarboxylation process significantly and, at the same time, permits the use of minored temperatures with respect to the thermal via. It has been also found that both the thermal and the microwave-assisted transformation can be developed under solvent-free conditions. (C) 2015 Elsevier Ltd. All rights reserved.
• Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status
  作者：Wei Tang、Anthony G. Borel、Tatsuya Fujimiya、Frank S. Abbott

  DOI：10.1021/tx00047a006

  日期：1995.7

  It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F-2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F-2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg); and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the (alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.