disodium;(2R)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate

• 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
• 英文名称: disodium;(2R)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate
• 化学式: C20H19N5Na2O6
• 分子量: 471.4
• InChiKey: NYDXNILOWQXUOF-FFXKMJQXSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -8.0
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

毒理性

• 肝毒性

培美曲塞治疗与血清酶水平低至中度升高有关，但这些通常较轻、短暂，且不伴有症状或黄疸。血清ALT或AST升高超过5倍ULN的患者占1%至6%，但通常病程自限，很少需要调整剂量或停药。没有报告因培美曲塞引起的临床明显的急性肝损伤病例。此外，培美曲塞尚未与 sinusoidal obSTruction syndrome (门脉高压症)或乙型肝炎的再激活有关联，但培美曲塞在高剂量用于肿瘤性疾病或骨髓移植的预处理方案中很少使用，而这些情况下其他肿瘤药物常与这些并发症有关。

Pemetrexed therapy is associated with a low-to-moderate rate of serum enzyme elevations, but these are generally mild, transient and without accompanying symptoms or jaundice. Serum ALT or AST elevations above 5 times ULN occur in 1% to 6% of patients, but are usually self-limited in course and rarely require dose modification or discontinuation. No instances of clinically apparent acute liver injury attributed to pemetrexed have been reported. In addition, pemetrexed has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which other neoplastic agents are commonly associated with these complications.

来源:LiverTox

反应信息

• 作为反应物：
  描述：

  disodium;(2R)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate 、 水 以 乙醇 为溶剂， 生成 disodium;(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate;heptahydrate
  参考文献：
  名称：

  NEW CRYSTALLINE FORM OF PEMETREXED DISODIUM

  摘要：

  本发明涉及Pemetrexed Disodium的新多形或晶体形式，其制备过程及其用途，特别是用于制备药物。

  公开号：

  US20120329819A1
• 作为产物：
  描述：

  disodium;(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate;heptahydrate 以 甲醇 为溶剂， 反应 12.0h， 以to afford 14.8 g of amorphous pemetrexed disodium的产率得到disodium;(2R)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate
  参考文献：
  名称：

  AMORPHOUS PEMETREXED DISODIUM

  摘要：

  制备无定形的培美曲塞二钠的过程，以及从无定形的培美曲塞二钠中去除残留溶剂的方法。

  公开号：

  US20110196154A1
• 作为试剂：
  描述：

  sodium hydroxide 、 N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰]-L-谷氨酸二乙酯对甲苯磺酸盐 、 盐酸 、 氯化钠 在 ice 、 disodium;(2R)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate 、 water ethanol 作用下， 以 水 为溶剂， 反应 7.58h， 以to give 3.19 g of pemetrexed disodium 2.5 hydrate in 81% yield as a white solid with a purity of 99.5%的产率得到tetrasodium;(2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate;pentahydrate
  参考文献：
  名称：

  One pot process for preparing pemetrexed disodium

  摘要：

  本发明涉及一种制备纯形式的抗叶酸类药物二甲双氢嘧啶二钠的一锅法过程。

  公开号：

  US08952153B2

文献信息

• [EN] AZOLE ANALOGUES AND METHODS OF USE THEREOF<br/>[FR] ANALOGUES DE COMPOSÉ DE TYPE AZOLE ET LEURS MÉTHODES D'UTILISATION
  申请人：UNIV CONNECTICUT

  公开号：WO2019040363A1

  公开（公告）日：2019-02-28

  Disclosed herein are analogues of itraconazole that are both angiogenesis and hedgehog signaling pathway inhibitors, formulations thereof, including lipsome formulations thereof. The compounds are expected to be useful in the treatment of cell proliferation disorders such as cancer, particularly cancers that are dependent upon the hedgehog signaling pathway such as basal cell carcinoma and medulloblastoma.

  本文披露了伊曲康唑的类似物，既是血管生成抑制剂，又是刺猬信号通路抑制剂，以及包括脂质体制剂在内的配方。这些化合物预计可用于治疗细胞增殖障碍，如癌症，特别是依赖于刺猬信号通路的癌症，如基底细胞癌和髓母细胞瘤。
• Process for Preparing Pemetrexed Disodium and Its Intermediate, 4-(4-Carbomethoxyphenyl) Butanal
  申请人：Li Jinliang

  公开号：US20110124861A1

  公开（公告）日：2011-05-26

  The present invention provides a process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl)butanal. The process for preparing the intermediate comprises the following steps: condensing methyl 4-bromobenzoate with 3-buten-1-ol; extracting with an organic solvent during the work-up; adding silica gel to decolorize; and evaporating the organic solvent to give 4-(4-carbomethoxyphenyl)butanal. The product obtained by the present process, with a yield of higher than 80%, and a purity measured by GC of higher than 95%, may be directly used in the next bromination reaction for synthesizing pemetrexed disodium without purification. The present process is suitable for industrial production, as the operation is simple and the reagents used are cheap and readily available.

  本发明提供了一种制备培美曲塞二钠及其中间体4-(4-羧甲氧基苯基)丁醛的方法。制备中间体的过程包括以下步骤：将甲基4-溴苯酸酯与3-丁烯-1-醇缩合；在工艺中进行有机溶剂萃取；加入硅胶脱色；蒸发有机溶剂得到4-(4-羧甲氧基苯基)丁醛。本工艺获得的产物收率高于80％，通过GC测得的纯度高于95％，可直接用于下一步溴化反应合成培美曲塞二钠而无需纯化。本工艺适用于工业生产，因其操作简单，所使用的试剂便宜且易得。
• PROCESSES FOR PREPARING PEMETREXED
  申请人：Kadaboina Rajasekhar

  公开号：US20130165654A1

  公开（公告）日：2013-06-27

  The present invention relates to pemetrexed disodium substantially free from specific process-related impurities, and processes for the preparation thereof.

  本发明涉及到基本没有特定工艺相关杂质的双氯酸培美曲塞钠，以及其制备方法。
• Process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl) butanal
  申请人：Li Jinliang

  公开号：US08507716B2

  公开（公告）日：2013-08-13

  The present invention provides a process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl)butanal. The process for preparing the intermediate comprises the following steps: condensing methyl 4-bromobenzoate with 3-buten-1-ol; extracting with an organic solvent during the work-up; adding silica gel to decolorize; and evaporating the organic solvent to give 4-(4-carbomethoxyphenyl)butanal. The product obtained by the present process, with a yield of higher than 80%, and a purity measured by GC of higher than 95%, may be directly used in the next bromination reaction for synthesizing pemetrexed disodium without purification. The present process is suitable for industrial production, as the operation is simple and the reagents used are cheap and readily available.

  本发明提供了一种制备培美曲塞二钠及其中间体4-(4-羧甲氧基苯基)丁醛的方法。制备中间体的过程包括以下步骤：将甲基4-溴苯酸酯与3-丁烯-1-醇缩合；在工作步骤中使用有机溶剂进行提取；加入硅胶进行脱色；蒸发有机溶剂以得到4-(4-羧甲氧基苯基)丁醛。本方法得到的产物收率高于80%，通过气相色谱测得的纯度高于95%，可以直接用于下一步致溴反应合成培美曲塞二钠而无需纯化。本方法适用于工业生产，因为操作简单，所用试剂便宜且易得。
• Crystalline form of pemetrexed disodium
  申请人：Albrecht Uwe Jens

  公开号：US09174991B2

  公开（公告）日：2015-11-03

  The present invention relates to a new polymorphic or crystalline form of Pemetrexed Disodium, processes for its preparation and its use, in particular for the preparation of medicaments.

  本发明涉及一种Pemetrexed Disodium的新多晶形或晶型，其制备过程及其用途，特别是用于制备药物。