(2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid | 439112-49-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid
• 英文别名: 3(R)-benzyloxymethyl-2(S)-(4-methoxyphenyl)pent-4-enoic acid；(R)-benzyloxymethyl-2(S)-(4-methoxy-phenyl)-pent-4-enoic acid；3(r)-Benzyloxymethyl-2-(s)-(4-methoxyphenyl)pent-4-enoic acid；(2S,3R)-2-(4-methoxyphenyl)-3-(phenylmethoxymethyl)pent-4-enoic acid
• CAS: 439112-49-9
• 化学式: C₂₀H₂₂O₄
• 分子量: 326.392
• InChiKey: JUTSISPZZJHJBJ-LPHOPBHVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid 在 sodium chlorite 、 sodium periodate 、 sodium dihydrogenphosphate 、 四氧化锇 、 2-甲基-2-丁烯 、 1-羟基苯并三唑 、 N-甲基吗啉氧化物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 、 叔丁醇 为溶剂， 反应 58.0h， 生成 (2R,3S)-2-(benzyloxymethyl)-N-[(S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-3-(4-methoxyphenyl)succinamic acid
  参考文献：
  名称：

  β-Aryl-Succinic Acid Hydroxamates as Dual Inhibitors of Matrix Metalloproteinases and Tumor Necrosis Factor Alpha Converting Enzyme

  摘要：

  Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFa levels with an ED50 of 1 mg/kg.

  DOI：

  10.1021/jm0110993
• 作为产物：
  描述：

  苄基丙炔基醚 在 盐酸 、 4-二甲氨基吡啶 、 三甲基氯硅烷 、 正己基锂 、 N,N'-二环己基碳二亚胺 、 红铝 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 25.22h， 生成 (2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid
  参考文献：
  名称：

  Process Development of a Dual MMP/TNF Inhibitor (SDZ 242-484)

  摘要：

  The compound (2R,3S)-N-4-((S)-2,2-Dimethyl-1-methylearbamoyl-propyl)-N-1-hydroxy-2-hydroxymethyl-3-(4-methoxy-phenyl)-succinamide (1; SDZ 242-484) shows antiinflammatory effects due to inhibition of matrix metalloproteases (MMP) and tumor necrosis factor-a activity (TNF). We describe the development of a chromatography-free process for a multikilogram-scale pilot-plant production. Two of the three chiral centers are introduced in a diastereoselective Claisen-Ireland rearrangement. It was found that the selectivity of this step was significantly enhanced by the addition of catalytic amounts of Lewis acids. The resulting enantiomeric carboxylic acids were resolved with (S)-(-)-phenylethylamine. The use of osmiumtetroxide was considered to be problematic for pilot-plant use. Therefore, it was necessary to rind an alternative method for the oxidative cleavage of the terminal olefin functionality. For the last chemical transformation, a hydrogenolytic cleavage of a benzyl group in the presence of a hydroxamate, a selective hydrogenation protocol was developed. To improve drug substance properties a series of hydroxamic acid salts were synthesized, and their physical behaviors were investigated.

  DOI：

  10.1021/op025536e

文献信息

• Hydroxamic acid derivatives
  申请人：Janser Philipp

  公开号：US20060063778A1

  公开（公告）日：2006-03-23

  Novel hydroxamic acid derivatives, e.g., of formula (I), wherein R 1 , R 2 , R 3 and R 4 are as defined, are found to be useful as pharmaceuticals, e.g., for the suppression of TNF release and the treatment of autoimmune and inflammatory diseases, e.g., multiple sclerosis and rheumatoid arthritis. Methods of making the compounds, novel intermediates, and pharmaceutical compositions comprising the compounds are provided.

  新型羟肟酸衍生物，例如公式（I）中的R1，R2，R3和R4所定义的衍生物，被发现可以作为药物使用，例如用于抑制TNF释放和治疗自身免疫和炎症性疾病，例如多发性硬化和类风湿性关节炎。提供了制备这些化合物的方法，新型中间体以及包含这些化合物的药物组合物。
• [EN] HYDROXAMIC ACID DERIVATIVES<br/>[FR] DERIVES DE L'ACIDE HYDROXAMIQUE
  申请人：——

  公开号：WO2003084941A3

  公开（公告）日：2004-03-25
• HYDROXAMIC ACID DERIVATIVES
  申请人：Novartis AG

  公开号：EP1497273B1

  公开（公告）日：2010-06-09
• US7589091B2
  申请人：——

  公开号：US7589091B2

  公开（公告）日：2009-09-15
• β-Aryl-Succinic Acid Hydroxamates as Dual Inhibitors of Matrix Metalloproteinases and Tumor Necrosis Factor Alpha Converting Enzyme
  作者：Georg Kottirsch、Guido Koch、Roland Feifel、Ulf Neumann

  DOI：10.1021/jm0110993

  日期：2002.5.1

  Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFa levels with an ED50 of 1 mg/kg.