(2R,3S)-N4-[(S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-N1-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide | 205807-59-6

• 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: (2R,3S)-N4-[(S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-N1-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
• 英文别名: SDZ 242-284；TNF484；Butanediamide, N1-((1S)-2,2-dimethyl-1-((methylamino)carbonyl)propyl)-N4-hydroxy-3-(hydroxymethyl)-2-(4-methoxyphenyl)-, (2S,3R)-；(2S,3R)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N'-hydroxy-3-(hydroxymethyl)-2-(4-methoxyphenyl)butanediamide
• CAS: 205807-59-6
• 化学式: C₁₉H₂₉N₃O₆
• 分子量: 395.456
• InChiKey: IOLRUMINDIUCLJ-RRFJBIMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  137
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid L-(-)-α-methylbenzylammonium salt 在 盐酸 、 sodium chlorite 、 sodium dihydrogenphosphate 、 2-甲基-2-丁烯 、 5%-palladium/activated carbon 、 (氯亚甲基)二甲基氯化铵 、 氢气 、 1-羟基苯并三唑 、 臭氧 、 N,N'-二异丙基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 叔丁醇 为溶剂， -78.0~23.0 ℃ 、110.0 kPa 条件下， 反应 27.42h， 生成 (2R,3S)-N4-[(S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-N1-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
  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

• 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.
• Process Development of a Dual MMP/TNF Inhibitor (SDZ 242-484)
  作者：Guido Koch、Georg Kottirsch、Bernhard Wietfeld、Ernst Küsters

  DOI：10.1021/op025536e

  日期：2002.9.1

  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.