N-methyl-N-((3S,4S)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine | 1206825-36-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: N-methyl-N-((3S,4S)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• 英文别名: N-methyl-N-[(3S,4S)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• CAS: 1206825-36-6
• 化学式: C₁₃H₁₉N₅
• 分子量: 245.327
• InChiKey: XRIARWQZLGCQDM-GXSJLCMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  56.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-methyl-N-((3S,4S)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 、 环丙乙酸 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 cis-2-cyclopropyl-1-(4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanone
  参考文献：
  名称：

  Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

  摘要：

  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.

  DOI：

  10.1021/jm1004286
• 作为产物：
  描述：

  4-羟基吡咯并[2,3-d]嘧啶 在 palladium on activated charcoal 、 水 、 氢气 、 sodium carbonate 、 potassium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 50.0~1000.0 ℃ 、303.99 kPa 条件下， 反应 16.0h， 生成 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

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。
• EFFICIENT METHOD FOR THE PREPARATION OF TOFACITINIB CITRATE
  申请人：OLON S.p.A.

  公开号：US20160297825A1

  公开（公告）日：2016-10-13

  Disclosed is a novel process for the synthesis of tofacitinib citrate on an industrial scale with high yields and purity starting with cis-(1-benzyl-4-methyl-piperidin-3-yl)methylamine bis-hydrochloride racemate (intermediate VIII), which comprises: 1. Condensation between intermediates VII and VIII to give intermediate VI 2. Hydrogenation of intermediate VI to give intermediate V 3. Resolution of intermediate V to give intermediate IV with enantiomeric purity >99% 4. Release of intermediate IV in a basic medium to give intermediate III 5. N-acylation reaction of intermediate III to give II (tofacitinib) 6. Salification of intermediate II to give tofacitinib monocitrate (I)

  揭示了一种新颖的工业规模合成托法替尼柠檬酸盐的方法，具有高产率和纯度，从顺式-(1-苄基-4-甲基哌啶-3-基)甲胺双盐酸盐(中间体VIII)开始，包括：1. 中间体VII和VIII之间的缩合反应形成中间体VI2. 中间体VI的加氢反应形成中间体V3. 中间体V的拆分反应形成对映纯度>99%的中间体IV4. 在碱性介质中释放中间体IV形成中间体III5. 中间体III的N-酰化反应形成II (托法替尼)6. 中间体II的盐化反应形成托法替尼单柠檬酸盐(I)
• 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.
• US9828380B2
  申请人：——

  公开号：US9828380B2

  公开（公告）日：2017-11-28
• 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.