霉酚酸甲酯 | 31858-66-9

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 中文名称: 霉酚酸甲酯
• 中文别名: 霉酚酸酯EP杂质E；霉酚酸酯杂质E
• 英文名称: methyl mycophenolate
• 英文别名: Mycophenolic acid methyl ester；methyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate；mycophenolic methyl ester；methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate；methyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
• CAS: 31858-66-9
• 化学式: C₁₈H₂₂O₆
• 分子量: 334.369
• InChiKey: ZPXRQFLATDNYSS-BJMVGYQFSA-N

物化性质

• 熔点：
  105-106°C
• 沸点：
  540.4±50.0 °C(Predicted)
• 密度：
  1.222±0.06 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、甲醇（微溶、超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  82.1
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 储存条件：
  | 室温 |

制备方法与用途

生物活性方面，甲基鸟苷酸（Methyl mycophenolate）是霉酚酸的甲酯衍生物，也存在于海生真菌Phaeosphaeria spartinae中。

反应信息

• 作为反应物：
  描述：

  霉酚酸甲酯 在 吡啶 、 2,3,5-三甲基吡啶 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 对甲苯磺酸 、 三乙胺 、 lithium iodide 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 156.75h， 生成 methyl (E)-6-(6-cyano-4-hydroxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
  参考文献：
  名称：

  Structure−Activity Relationships for Inhibition of Inosine Monophosphate Dehydrogenase by Nuclear Variants of Mycophenolic Acid

  摘要：

  Structure-activity relationships in the region of the phthalide ring of the inosine monophosphate dehydrogenase inhibitor mycophenolic acid have been explored. Replacement of the lactone ring with other cyclic moieties resulted in loss of potency, especially for larger groups. Replacement of the ring by acyclic substituents also indicated a strong sensitivity to steric bulk. A phenolic hydroxyl group, with an adjacent hydrogen bond acceptor, was found to be essential for high potency. The aromatic methyl group was essential for activity; the methoxyl group could be replaced by ethyl to give a compound with 2-4 times the potency of mycophenolic acid in vitro and in vivo.

  DOI：

  10.1021/jm9603633
• 作为产物：
  描述：

  methyl (E)-6-(6-methoxy-7-methyl-3-oxo-4-((2-(trimethylsilyl)ethoxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate 在 硫酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 0.75h， 以88%的产率得到霉酚酸甲酯
  参考文献：
  名称：

  A convergent synthesis of Mycophenolic acid

  摘要：

  A new method for the synthesis of Mycophenolic acid using a convergent approach has been developed where the key step is a palladium mediated allyl-aryl tin coupling. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4020(97)00061-6

文献信息

• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• Synthesis of propargylamine mycophenolate analogues and their selective cytotoxic activity towards neuroblastoma SH-SY5Y cell line
  作者：Patamawadee Silalai、Dumnoensun Pruksakorn、Arthit Chairoungdua、Kanoknetr Suksen、Rungnapha Saeeng

  DOI：10.1016/j.bmcl.2021.128135

  日期：2021.8

  Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A3-coupling reaction. Their cytotoxic activity was examined against six cancer cell lines. Compounds 6a, 6j, 6t, 6u, and 6z exhibited selective cytotoxicity towards neuroblastoma (SH-SY5Y) cancer cells and were less toxic to normal cells in comparison to the lead compound, MPA

  采用关键步骤A 3 -偶联反应，由霉酚酸1设计并合成了26种炔丙胺霉酚酸酯类似物。针对六种癌细胞系检查了它们的细胞毒活性。与先导化合物 MPA 1和标准药物玫瑰树碱相比，化合物6a、6j、6t、6u和6z对神经母细胞瘤 (SH-SY5Y) 癌细胞表现出选择性细胞毒性，并且对正常细胞的毒性较小。分子对接结果表明化合物6a非常适合作为癌症治疗靶点的三种蛋白质（CDK9、EGFR 和 VEGFR-2）的关键氨基酸。炔丙胺霉酚酸酯支架可能是开发新的神经母细胞瘤抗癌药物的一个有价值的起点。
• 一种磷酰胺衍生物及制备方法和用途
  申请人：四川海思科制药有限公司

  公开号：CN109305989B

  公开（公告）日：2021-02-26

  本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐，以及在制备用于预防或治疗糖尿病、抗肿瘤、多动运动障碍、运动神经元疾病、脑保护、与中枢神经系统相关疾病、免疫抑制、器官组织或细胞异体抑制排斥反应、免疫调节和/或炎性疾病、惊厥、癫痫或脑卒中药物中的应用，通式(I)化合物的结构为Q‑L‑R1，其基团定义与说明书定义一致。
• Diels–Alder and Stille Coupling Approach for the Short Protecting-Group-Free Synthesis of Mycophenolic Acid, Its Phenylsulfenyl and Phenylselenyl Analogues, and Reactive Oxygen Species (ROS) Probing Capacity in Water
  作者：Mahesh B. Halle、Tesla Yudhistira、Woo-Hyun Lee、Sandip V. Mulay、David G. Churchill

  DOI：10.1021/acs.orglett.8b01327

  日期：2018.6.15

  Stille cross-coupling approach includes key transformations, allowing for a competitive synthesis which involves a rare halophenol Stille cross-coupling study. The phenylselenyl and phenylsulfenyl analogues were prepared as novel compounds in good overall yield. The applicability of one of the intermediates as a potential probe for reactive oxygen species (ROS) in water is investigated.

  实现了短的，无保护基团的合成。该合成是步高效且通用的。Diels-Alder和Stille交叉偶联方法包括关键的转变，可以进行竞争性合成，其中涉及罕见的卤代酚Stille交叉偶联研究。以良好的总收率将苯基硒烯基和苯基硫烯基类似物制备为新型化合物。研究了其中一种中间体作为水中活性氧（ROS）潜在探针的适用性。
• Convenient syntheses of the in vivo carbohydrate metabolites of mycophenolic acid: reactivity of the acyl glucuronide
  作者：Amy E. Jones、Helen K. Wilson、Paul Meath、Xiaoli Meng、David W. Holt、Atholl Johnston、Michael Oellerich、Victor W. Armstrong、Andrew V. Stachulski

  DOI：10.1016/j.tetlet.2009.06.060

  日期：2009.9

  Following in vivo use of mycophenolic acid, the O-aryl and O-acyl glucuronides, as well as the recently discovered O-aryl glucoside (Scheme 1), are all found as metabolites. We describe convenient preparations of all three derivatives. The phenolic glycosides are obtained by phase-transfer-catalysed alkylation of methyl mycophenolate in very high yield, as an excellent alternative to the Königs-Knorr

  在体内使用麦考酚酸后，O-芳基和O-酰基葡糖醛酸苷以及最近发现的O-芳基葡糖苷（方案1）均被发现是代谢产物。我们描述了所有三种衍生物的方便制备方法。酚类糖苷是通过相转移催化的麦考酚酸甲酯烷基化获得的，产率很高，可作为柯尼希斯-克诺尔反应的绝佳替代品。我们仔细优化了早期的酰基葡糖醛酸苷合成方法，从而以更高的收率获得了高纯度的产品。最后，我们描述了合成酰基葡糖醛酸苷在证明其对已知靶蛋白的反应性方面具有对天然获得的物质的优异响应的价值。