1,4-dimethyl but-2-enedioate | 23055-10-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 1,4-dimethyl but-2-enedioate
• 英文别名: dimethyl fumarate；dimethyl maleate；DMF；dimethyl butenedioate；Dimethyl but-2-enedioate
• CAS: 23055-10-9
• 化学式: C₆H₈O₄
• 分子量: 144.127
• InChiKey: LDCRTTXIJACKKU-UHFFFAOYSA-N

物化性质

• 熔点：
  101-102 °C (sublm)
• 沸点：
  215-220 °C
• 密度：
  1.124±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

毒理性

• 肝毒性

在大规模随机对照试验中，对银屑病和多发性硬化症患者使用二甲基富马酸盐，血清ALT升高是常见的，发生在多达25%的患者中。然而，这些升高通常是轻到中度的，即使没有调整剂量也能迅速解决。与安慰剂接受者相比，二甲基富马酸盐的升高超过3倍ULN的发生率为6%，而安慰剂为3%至6%。酶升高通常是短暂的，不伴有症状或黄疸，需要停药的患者不到1%。在甲基富马酸盐的预注册试验中没有报告急性肝炎或临床上明显的肝损伤的病例。尽管如此，在其批准后2到3年内，随着更广泛的使用，报告了几例临床上明显的肝损伤伴黄疸的病例。大多数病例在开始使用二甲基富马酸盐后的2到3个月内发生，但也报告了一些潜伏期较长的病例。典型病例表现为急性肝炎样特征，血清转氨酶水平显著升高，碱性磷酸酶升高仅适度。免疫过敏特征和自身抗体并不常见，所有患者在停药后都恢复，没有报告慢性损伤或肝衰竭的实例。 临床上明显的肝损伤在使用二噁烷或单甲基富马酸盐时并未报告，但这些药物的临床经验有限。由于这三种单甲基富马酸盐的前药的副作用概况相似，因此怀疑这三种药物都是临床上明显肝损伤的罕见原因。 二甲基富马酸盐的可能性评分：C（可能是临床上明显肝损伤的罕见原因）。 二噁烷富马酸盐的可能性评分：E*（未证实但怀疑是临床上明显肝损伤的罕见原因）。 单甲基富马酸盐的可能性评分：E*（未证实但怀疑是临床上明显肝损伤的罕见原因）。

In large randomized controlled trials of dimethyl fumarate in patients with psoriasis and multiple sclerosis, serum ALT elevations were frequent, occurring in up to 25% of patients. The elevations, however, were generally mild-to-moderate and resolved rapidly even without dose modification. Elevations above 3 times ULN were reported in 6% of dimethyl fumarate compared to 3% to 6% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice, requiring drug discontinuation in less than 1% of patients. No cases of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of methyl fumarate. Despite this, several cases of clinically apparent liver injury with jaundice were reported within 2 to 3 years of its approval and more widescale use. Most cases occurred within 2 to 3 months of starting dimethyl fumarate but some instances with more prolonged latency were reported. The typical case presented with acute hepatitis like features, marked increases in serum aminotransferase levels, and only modest alkaline phosphatase elevations. Immunoallergic features and autoantibodies were not frequent and all patients recovered upon stopping the medication with no reported instances of chronic injury or hepatic failure. Cases of clinically apparent liver injury have not been reported with diroximel or monomethyl fumarate but the clinical experience with these agents has been limited. Because the side effect profiles of these three pro-drugs of monomethyl fumarate are similar, it is suspected that all three are rare causes of clinically apparent liver injury. Likelihood score for dimethyl fumarate: C (probable rare cause of clinically apparent liver injury). Likelihood score for diroximel fumarate: E* (unproven but suspected rare cause of clinically apparent liver injury). Likelihood score for monomethyl fumarate: E* (unproven but suspected rare cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：目前没有关于哺乳期间使用二甲双胍的临床信息。然而，二甲双胍的活性代谢物单甲基双胍在母乳中的量似乎很低，预计不会对哺乳婴儿造成任何不良反应。在有任何数据之前，一些作者建议在二甲双胍治疗期间避免哺乳，而其他作者和美国制造商则不这么认为。哺乳婴儿应被监测体重增长和发育里程碑，特别是在较年轻、仅以母乳为食的婴儿中。一些作者还建议监测哺乳婴儿是否有潮红、呕吐和腹泻的情况。 哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the clinical use of dimethyl fumarate during breastfeeding. However, amounts of the active metabolite of dimethyl fumarate, monomethyl fumarate, in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. Before any data were available, some authors recommend avoiding breastfeeding during dimethyl fumarate therapy, others and the US manufacturer did not. Breastfed infants should be monitored for adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Some authors also recommend monitoring breastfed infants for flushing, vomiting and diarrhea. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

反应信息

• 作为反应物：
  描述：

  1,4-dimethyl but-2-enedioate 在 sodium hydroxide 、 sodium hypochlorite 作用下， 生成 3-Isopropylisoxazole-4,5-dicarboxylic acid 4-methyl ester
  参考文献：
  名称：

  Synthesis and herbicidal activity of isoxazoledicarboxylic acid derivatives

  摘要：

  AbstractStarting from bulk chemicals, novel isoxazoledicarboxylic acid esters were prepared and converted to the corresponding dicarboxylic acid mono‐amides in a few reaction steps and in high overall yields. Key intermediates for the cycloaddition step were chlorooximinoacetates or amides as nitrile oxide equivalents, prepared in one‐pot reactions from diketene or acetoacetic acid esters. Isoxazoledicarboxylic acid monoamides combined good herbicidal activity with chemical flexibility. They were characterized as inhibitors of photosynthesis. Particularly, they affected the photosynthetic electron transport in photosystem II and the rate of carbon dioxide assimilation. Applied post‐emergence, the new compounds were found to control a broad spectrum of key weeds in corn. Excellent activity was found on Abutilon theophrasti (L.) Medik., Amaranthus retroflexus L., Chenopodium album L., Ipomoea spp., Polygonum persicaria L., Solanum nigrum L. and Xanthium strumarium L. with rates between 0.2 and 0.5 kg ha−1. As a side‐effect, the compounds also showed activity against grass weeds. The compounds are excellent tank‐mix partners, e.g. for sulfonyl‐ureas, to complete the weed spectrum (Chenopodium album L., Solanum nigrum L.) and/or to reduce the risk of developing herbicide‐resistant weeds.

  DOI：

  10.1002/ps.2780440104
• 作为产物：
  描述：

  丁炔二酸二甲酯 在 二甲基苯基硅烷 、 水 作用下， 以 乙腈 为溶剂， 反应 1.5h， 以80%的产率得到1,4-dimethyl but-2-enedioate
  参考文献：
  名称：

  Nanoporous Gold Catalyst for Highly Selective Semihydrogenation of Alkynes: Remarkable Effect of Amine Additives

  摘要：

  We report for the first time the highly selective semihydrogenation of alkynes using the unsupported nanoporous gold (AuNPore) as a catalyst and organosilanes with water as a hydrogen source. Under the optimized reaction conditions, the present semihydrogenation of various terminal- and internal-alkynes affords the corresponding alkenes in high chemical yields and excellent Z-selectivity without any, over-reduced alkanes. The use of DMF as solvent, which generates amines in situ, or pyridine as an additive is crucial to suppress the association of hydrogen atoms on AuNPore to form H-2 gas, which is unable to reduce alkynes on the unsupported gold catalysts. The AuNPore catalyst can be readily recovered and reused without any loss of catalytic activity. In addition, the SEM and TEM characterization of nanoporosity show that the AuNPore catalyst has a bicontinuous 3D structure and a high density of atomic steps and kinks on ligament surfaces, which should be one of the important origins of catalytic activity.

  DOI：

  10.1021/ja3087592
• 作为试剂：
  描述：

  2,2'-联吡啶 、 2-苯基-4-喹啉羧酸 、 cobalt(II) acetate 在 1,4-dimethyl but-2-enedioate 作用下， 以 甲醇 为溶剂， 反应 96.0h， 以76%的产率得到[Co3(2-phenyl-4-quinolinecarboxylate)6(2,2'-bipyridyl)2]
  参考文献：
  名称：

  三种基于 2-苯基-4-喹啉羧酸和含氮中性配体的新型配位化合物：合成、结构特征和性质

  摘要：

  2-苯基-4-喹啉羧酸 (Hpqba) 与 CdII、CoII、ZnII 和/或 4,4'-联吡啶 (4,4'-bipy)、1,4-双(咪唑-1-基甲基) 的溶剂热反应苯 (biyb), 2,2'-bipyridyl (2,2'-bipy) 提供三种新的化学计量配位化合物 [Cd(pqba)2(4,4'-bipy)] (1), [Zn(pqba) 2biyb] (2) 和 [Co3(pqba)6-(2,2'-bipy)2] (3)。通过元素分析、红外光谱、热重分析和单晶 X 射线衍射研究对化合物 1-3 进行了表征。化合物1具有二维结构，而化合物2由一维（1D）网络组成，通过π…π堆积相互作用进一步扩展，形成3D超分子结构。配合物 3 也表现出完全基于 π···π 堆积相互作用的 3D 超分子结构。pqba 配体采用 μ1-k1,k1, μ1-k1, μ2-k1,k1, and μ2-k1

  DOI：

  10.1002/zaac.201300169

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• Visible-Light Photoredox-Catalyzed Giese Reaction: Decarboxylative Addition of Amino Acid Derived α-Amino Radicals to Electron-Deficient Olefins
  作者：Anthony Millet、Quentin Lefebvre、Magnus Rueping

  DOI：10.1002/chem.201602257

  日期：2016.9.12

  A tin‐ and halide‐free, visible‐light photoredox‐catalyzed Giese reaction was developed. Primary and secondary α‐amino radicals were generated readily from amino acids in the presence of catalytic amounts of an iridium photocatalyst. The reactivity of the α‐amino radicals has been evaluated for the functionalization of a variety of activated olefins.

  开发了一种无锡和无卤可见光氧化还原催化的Giese反应。在催化量的铱光催化剂存在下，氨基酸很容易产生伯和仲α-氨基。已经评估了α-氨基自由基的反应性，以用于各种活化烯烃的功能化。
• [EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
  申请人：ALMIRALL SA

  公开号：WO2017220431A1

  公开（公告）日：2017-12-28

  Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

  公开了式（I）的新型融合吡唑衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为Janus激酶（JAK）抑制剂在治疗中的用途。
• PROGRAMMABLE THERMORESPONSIVE GELS
  申请人：City of Hope

  公开号：US20200121598A1

  公开（公告）日：2020-04-23

  Provided herein, inter alia, are non-crosslinked polymers that possess thermoresponsive properties. These polymers possess a cleavable bond that breaks under certain conditions The disclosure also provides pharmaceutical compositions containing the polymers and therapeutic agents, methods for delivering the therapeutic agents, and kits, syringes, and catheters containing the polymer compositions and therapeutic agents.

  本文提供了具有热响应性能的非交联聚合物。这些聚合物具有在特定条件下断裂的可切割键。该公开还提供了含有这些聚合物和治疗剂的药物组合物、传递治疗剂的方法，以及含有聚合物组合物和治疗剂的工具包、注射器和导管。
• Synthesis of Aporphine Analogues via Palladium-Catalyzed Intramolecular Aryl–Aryl Dehydrogenative Coupling
  作者：Chen Su、Wen-Hua Xu、Rui-Li Guo、Xing-Long Zhang、Xue-Qing Zhu、Ya-Ru Gao、Yong-Qiang Wang

  DOI：10.1021/acs.joc.1c01649

  日期：2021.10.1

  Reported herein is an intramolecular dehydrogenative coupling of two inert aryl C–H bonds for the synthesis of aporphine analogues. The process represents a novel tool for the preparation of aporphines via palladiun-catalyzed C–H bond activation. The present reaction is compatible with various functional groups, and the coupling products have been further applied for the synthesis of natural products

  本文报道了用于合成阿朴啡类似物的两个惰性芳基 C-H 键的分子内脱氢偶联。该过程代表了一种通过钯催化的 C-H 键活化制备阿朴啡的新工具。本反应与多种官能团相容，偶联产物已进一步应用于天然产物阿朴啡和zenkerine的合成。