(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)pentanoic acid cyclohexylammonium salt | 414869-76-4

• 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: (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)pentanoic acid cyclohexylammonium salt
• 英文别名: (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid cyclohexylamine salt；cyclohexanamine;(2R)-5-(3-methyl-4-phenylphenyl)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pentanoic acid
• CAS: 414869-76-4
• 化学式: C₆H₁₃N*C₂₄H₃₀O₄
• 分子量: 481.676
• InChiKey: VMUBTJUGRXDHPI-VEIFNGETSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)pentanoic acid cyclohexylammonium salt 在 柠檬酸 作用下， 以 二氯甲烷 、 水 为溶剂， 以100%的产率得到tert-butyl (3R)-3-(carboxy)-6-(3-methyl-4-phenylphenyl)hexanoate
  参考文献：
  名称：

  Asymmetric Synthesis of an MMP-3 Inhibitor Incorporating a 2-Alkyl Succinate Motif

  摘要：

  An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent (11), which was reacted with the phosphonosuccinate (10) to selectively afford the trans-b-substituted itaconate (12). Catalytic asymmetric hydrogenation of the itaconate (12) was achieved in good conversion and with 86-96% enantiomeric excess with a range of phosphine-modified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate (2) was elaborated to the desired drug substance (1) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of (1) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.

  DOI：

  10.1021/op034001y
• 作为产物：
  描述：

  5-溴-2-碘甲苯 在 sodium disulfite 、 ((-)-(1S)-[1,1'-binaphthalene]-2,2'-diylbis[diphenylphosphine-κP])chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]ruthenium(1+) chloride 、 potassium tert-butylate 、 四丁基氯化铵 、 氢气 、 palladium diacetate 、 碳酸氢钠 、 sodium carbonate 、 三苯基膦 、 三(邻甲基苯基)磷 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 丙酮 、 乙腈 、 叔丁醇 为溶剂， -5.0~60.0 ℃ 、413.7 kPa 条件下， 反应 108.17h， 生成 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)pentanoic acid cyclohexylammonium salt
  参考文献：
  名称：

  Asymmetric Synthesis of an MMP-3 Inhibitor Incorporating a 2-Alkyl Succinate Motif

  摘要：

  An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent (11), which was reacted with the phosphonosuccinate (10) to selectively afford the trans-b-substituted itaconate (12). Catalytic asymmetric hydrogenation of the itaconate (12) was achieved in good conversion and with 86-96% enantiomeric excess with a range of phosphine-modified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate (2) was elaborated to the desired drug substance (1) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of (1) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.

  DOI：

  10.1021/op034001y

文献信息

• Novel olefination process to itaconate and succinate derivatives
  申请人：——

  公开号：US20020058832A1

  公开（公告）日：2002-05-16

  An efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (IV), and/or succinate derivatives of formula (V) and/or (VI) by asymmetric hydrogenation of the itaconate derivatives. 1

  一种高效且选择性的工艺，可扩大规模，通过对顺丁烯二酸衍生物进行不对称加氢，制备化学式（IV）的顺丁烯二酸衍生物，以及/或化学式（V）和/或（VI）的琥珀酸衍生物。
• Olefination process to itaconate and succinate derivatives
  申请人：Pfizer Inc.

  公开号：US06452041B1

  公开（公告）日：2002-09-17

  An efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (IV), and/or succinate derivatives of formula (V) and/or (VI) by asymmetric hydrogenation of the itaconate derivatives. wherein R, R1 and R2 are as defined herein.

  一种高效且选择性的工艺，能够扩大规模，通过对顺式丁烯二酸衍生物进行不对称氢化反应，制备公式（IV）的顺式丁烯二酸衍生物，以及公式（V）和/或（VI）的琥珀酸衍生物，其中R，R1和R2如本文所定义。
• US6452041B1
  申请人：——

  公开号：US6452041B1

  公开（公告）日：2002-09-17
• US6750363B2
  申请人：——

  公开号：US6750363B2

  公开（公告）日：2004-06-15
• Asymmetric Synthesis of an MMP-3 Inhibitor Incorporating a 2-Alkyl Succinate Motif
  作者：Christopher P. Ashcroft、Stephen Challenger、Andrew M. Derrick、Richard Storey、Nicholas M. Thomson

  DOI：10.1021/op034001y

  日期：2003.5.1

  An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent (11), which was reacted with the phosphonosuccinate (10) to selectively afford the trans-b-substituted itaconate (12). Catalytic asymmetric hydrogenation of the itaconate (12) was achieved in good conversion and with 86-96% enantiomeric excess with a range of phosphine-modified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate (2) was elaborated to the desired drug substance (1) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of (1) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.