4-methoxyphenylacetic acid (E)-4-(benzyloxy)but-2-enyl ester | 439112-48-8

• 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: 4-methoxyphenylacetic acid (E)-4-(benzyloxy)but-2-enyl ester
• 英文别名: (4-methoxyphenyl)acetic acid 4-benzyloxybut-2-enyl ester；trans-(4-methoxy-phenyl)-acetic acid 4-benzyloxy-but-2-enyl ester；[(E)-4-phenylmethoxybut-2-enyl] 2-(4-methoxyphenyl)acetate
• CAS: 439112-48-8
• 化学式: C₂₀H₂₂O₄
• 分子量: 326.392
• InChiKey: CYXCFYHETOSYBV-AATRIKPKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-methoxyphenylacetic acid (E)-4-(benzyloxy)but-2-enyl ester 在 三甲基氯硅烷 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 乙酸乙酯 为溶剂， 反应 3.22h， 生成 (2S,3R)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid L-(-)-α-methylbenzylammonium salt
  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
• 作为产物：
  描述：

  苄基丙炔基醚 在 4-二甲氨基吡啶 、 正己基锂 、 N,N'-二环己基碳二亚胺 、 红铝 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 22.0h， 生成 4-methoxyphenylacetic acid (E)-4-(benzyloxy)but-2-enyl ester
  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

• Highly diastereoselective Lewis acid promoted Claisen–Ireland rearrangement
  作者：Guido Koch、Philipp Janser、Georg Kottirsch、Eva Romero-Giron

  DOI：10.1016/s0040-4039(02)00864-x

  日期：2002.7

  In the presence of catalytic amounts of Lewis acids silyl ketene acetals of trans allylic esters undergo a highly diastereoselective Claisen–Ireland rearrangement to the corresponding disubstituted γ-δ-unsaturated erythro carboxylic acids. Diastereoselectivities of up to 15:1 were achieved when using TiCl4 as catalyst. The uncatalyzed process proceeds slowly and with significantly lower selectivity

  在催化量的路易斯酸存在下，反式烯丙基酯的甲硅烷基烯酮缩醛会发生高度非对映选择性的克莱森-爱尔兰重排反应，生成相应的二取代的γ-δ-不饱和赤型羧酸。当使用TiCl 4作为催化剂时，非对映选择性达到15：1 。未催化的过程缓慢进行，选择性大大降低。宽范围的芳基和烷基取代基是可以接受的。
• 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
• 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.
• HYDROXAMIC ACID DERIVATIVES
  申请人：Novartis AG

  公开号：EP1497273B1

  公开（公告）日：2010-06-09