托法替尼杂质N | 1252883-90-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 托法替尼杂质N
• 中文别名: 托法替尼杂质 N
• 英文名称: N-((3S,4S)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrro-lo[2,3-d]pyrimidin-4-amine
• 英文别名: N-((3S,4S)-1-Benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine；N-[(3S,4S)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• CAS: 1252883-90-1
• 化学式: C₂₀H₂₅N₅
• 分子量: 335.452
• InChiKey: UMWNXPTXDOVDFE-MAUKXSAKSA-N

物化性质

• 熔点：
  >66°C (dec.)
• 密度：
  1.205±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)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  48
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  托法替尼杂质N 在 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 、 水 为溶剂， 50.0 ℃ 、303.99 kPa 条件下， 以80%的产率得到N-methyl-N-((3S,4S)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  一种N-甲基-N-(4-甲基哌啶)-3-基-7H-吡咯并嘧啶-4-胺的制备方法

  摘要：

  本发明涉及一种N‑甲基‑N‑(4‑甲基哌啶)‑3‑基‑7H‑吡咯并嘧啶‑4‑胺的新的合成路线，分别以4‑甲基‑3‑哌啶酮和4‑羟基‑6,7‑二氢‑5H‑吡咯并[2,3‑D]嘧啶为原料，经六步反应高产率合成托法替尼关键中间体N‑甲基‑N‑((3R,4R)‑4‑甲基哌啶‑3‑基)‑7H‑吡咯并[2,3‑D]嘧啶‑4‑胺。本发明提供的托法替尼关键中间体N‑甲基‑N‑((3R,4R)‑4‑甲基哌啶‑3‑基)‑7H‑吡咯并[2,3‑D]嘧啶‑4‑胺的制备方法是一种高收率、高手性纯度、低成本、环保、易操作、适宜工业化的制备方法。

  公开号：

  CN110204549A
• 作为产物：
  描述：

  4-羟基吡咯并[2,3-d]嘧啶 在 水 、 sodium carbonate 、 potassium carbonate 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 16.0h， 生成 托法替尼杂质N
  参考文献：
  名称：

  一种N-甲基-N-(4-甲基哌啶)-3-基-7H-吡咯并嘧啶-4-胺的制备方法

  摘要：

  本发明涉及一种N‑甲基‑N‑(4‑甲基哌啶)‑3‑基‑7H‑吡咯并嘧啶‑4‑胺的新的合成路线，分别以4‑甲基‑3‑哌啶酮和4‑羟基‑6,7‑二氢‑5H‑吡咯并[2,3‑D]嘧啶为原料，经六步反应高产率合成托法替尼关键中间体N‑甲基‑N‑((3R,4R)‑4‑甲基哌啶‑3‑基)‑7H‑吡咯并[2,3‑D]嘧啶‑4‑胺。本发明提供的托法替尼关键中间体N‑甲基‑N‑((3R,4R)‑4‑甲基哌啶‑3‑基)‑7H‑吡咯并[2,3‑D]嘧啶‑4‑胺的制备方法是一种高收率、高手性纯度、低成本、环保、易操作、适宜工业化的制备方法。

  公开号：

  CN110204549A

文献信息

• Methyl-α-d-glucopyranoside as Green Ligand for Selective Copper-Catalyzed N-Arylation
  作者：Yuanguang Chen、Fangyu Du、Fengyang Chen、Qifan Zhou、Guoliang Chen

  DOI：10.1055/s-0039-1690702

  日期：2019.12

  selective N-arylation of amines or azoles with aryl halides­, methyl-α-d-glucopyranoside (MG) was found to function as a green ligand of copper powder. In addition, nitrogen heterocyclic amine compounds can also undergo the N-arylation coupling with heterocyclic aryl chlorides. This process allows access to a variety of aromatic amines and aryl azoles under mild reaction conditions, has good tolerance, and

  在胺或唑与芳基卤的选择性N-芳基化反应中，发现甲基-α - d-吡喃葡萄糖苷（MG）作为铜粉的绿色配体起作用。另外，氮杂环胺化合物还可与杂环芳基氯进行N-芳基化偶联。该方法允许在温和的反应条件下获得各种芳族胺和芳基唑，具有良好的耐受性，并且以中等至高收率进行。
• [EN] PIPERIDINE INHIBITORS OF JANUS KINASE 3<br/>[FR] INHIBITEURS PIPÉRIDINIQUES DE LA JANUS KINASE 3
  申请人：AUSPEX PHARMACEUTICALS LLC

  公开号：WO2010123919A3

  公开（公告）日：2011-03-03
• Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection
  作者：Mark E. Flanagan、Todd A. Blumenkopf、William H. Brissette、Matthew F. Brown、Jeffrey M. Casavant、Chang Shang-Poa、Jonathan L. Doty、Eileen A. Elliott、Michael B. Fisher、Michael Hines、Craig Kent、Elizabeth M. Kudlacz、Brett M. Lillie、Kelly S. Magnuson、Sandra P. McCurdy、Michael J. Munchhof、Bret D. Perry、Perry S. Sawyer、Timothy J. Strelevitz、Chakrapani Subramanyam、Jianmin Sun、David A. Whipple、Paul S. Changelian

  DOI：10.1021/jm1004286

  日期：2010.12.23

  There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
• Examining the Chirality, Conformation and Selective Kinase Inhibition of 3-((3<i>R</i>,4<i>R</i>)-4-methyl-3-(methyl(7H-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)
  作者：Jian-kang Jiang、Kamran Ghoreschi、Francesca Deflorian、Zhi Chen、Melissa Perreira、Marko Pesu、Jeremy Smith、Dac-Trung Nguyen、Eric H. Liu、William Leister、Stefano Costanzi、John J. O’Shea、Craig J. Thomas

  DOI：10.1021/jm801142b

  日期：2008.12.25

  Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.