(±)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid

• 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: (±)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid
• 英文别名: 3-benzyloxymethyl-2-(4-methoxy-phenyl)-pent-4-enoic acid；(2R,3S)-2-(4-methoxyphenyl)-3-(phenylmethoxymethyl)pent-4-enoic acid
• 化学式: C₂₀H₂₂O₄
• 分子量: 326.392
• InChiKey: JUTSISPZZJHJBJ-VQIMIIECSA-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：

  (±)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid 在 盐酸 、 sodium chlorite 、 sodium dihydrogenphosphate 、 2-甲基-2-丁烯 、 (氯亚甲基)二甲基氯化铵 、 臭氧 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 甲苯 、 叔丁醇 为溶剂， 反应 22.17h， 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：

  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 、 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 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 25.22h， 生成 (±)-3-(benzyloxymethyl)-2-(4-methoxyphenyl)pent-4-enoic acid 、 (±)-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

• 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。
• [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
• 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.