(1R,2R,4R)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl isobutyrate | 1075744-31-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: (1R,2R,4R)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl isobutyrate
• 英文别名: ACT-280778；isobutyric acid (1R,2R,4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester；rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester；[(1R,2R,4R)-2-[2-[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-5-phenyl-2-bicyclo[2.2.2]oct-5-enyl] 2-methylpropanoate
• CAS: 1075744-31-8
• 化学式: C₃₃H₄₃N₃O₄
• 分子量: 545.722
• InChiKey: PEBSFLONQDNKQK-PHLCOOFXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  76.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R,2R,4R)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl isobutyrate 、 顺丁烯二酸 以 甲醇 、 乙醇 、 乙酸乙酯 为溶剂， 反应 2.75h， 以9.4 kg的产率得到(1R,2R,4R)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl isobutyrate dimaleate
  参考文献：
  名称：

  Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT-280778

  摘要：

  A scalable access to 1 (ACT-280778), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (3) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to the success of this fit-for-purpose approach are a robust and atom-efficient access to benzimidazole 4, the substrate-controlled diastereoselective enolate addition toward carboxylic acid 2 that was isolated by simple crystallization with high dr (>99:1), the convenient selective N-deacylation of intermediate 10, and the identification of a suitable solid form of 1 as the bis-maleate salt (1 center dot 2 C4H4O4). As an illustration of the robustness of this process, 14 kg of drug substance, suitable for human use, was produced with an overall yield of 38% over the longest linear sequence (7 steps).

  DOI：

  10.1021/op400269b
• 作为产物：
  描述：

  在 甲醇 、 sodium methylate 作用下， 以 2-甲基四氢呋喃 为溶剂， 反应 1.0h， 以8.79 kg的产率得到(1R,2R,4R)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-5-phenylbicyclo[2.2.2]oct-5-en-2-yl isobutyrate
  参考文献：
  名称：

  Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT-280778

  摘要：

  A scalable access to 1 (ACT-280778), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (3) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to the success of this fit-for-purpose approach are a robust and atom-efficient access to benzimidazole 4, the substrate-controlled diastereoselective enolate addition toward carboxylic acid 2 that was isolated by simple crystallization with high dr (>99:1), the convenient selective N-deacylation of intermediate 10, and the identification of a suitable solid form of 1 as the bis-maleate salt (1 center dot 2 C4H4O4). As an illustration of the robustness of this process, 14 kg of drug substance, suitable for human use, was produced with an overall yield of 38% over the longest linear sequence (7 steps).

  DOI：

  10.1021/op400269b

文献信息

• BENZIMIDAZOLE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
  申请人：Hubler Francis

  公开号：US20110039905A1

  公开（公告）日：2011-02-17

  The invention relates to compounds of formula (I) wherein R 1 represents aryl, which is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and trifluoromethyl; R 2 represents hydrogen, or —CO—R 21 ; R 21 represents (C 1-5 )alkyl, (C 1-3 )fluoroalkyl, or (C 3-6 )cycloalkyl; m represents the integer 2, or 3; p represents the integer 2 or 3; and R 3 represents hydrogen, or (C 1-5 )alkyl; and pharmaceutically acceptable salts of such compounds. These compounds are useful as calcium channel blockers.

  该发明涉及以下式(I)的化合物，其中R1代表芳基，未取代，或者单取代、双取代或三取代，其中取代基独立地选自(C1-4)烷基，(C1-4)氧烷基，卤素和三氟甲基组成的组；R2代表氢，或者—CO—R21；R21代表(C1-5)烷基，(C1-3)氟烷基或(C3-6)环烷基；m表示整数2或3；p表示整数2或3；和R3代表氢，或者(C1-5)烷基；以及这些化合物的药用盐。这些化合物可用作钙通道阻滞剂。
• SALTS OF ISOBUTYRIC ACID (1 R*,2R*,4R*) -2- (2- - ETHYL)-5-PHENYL-BICYCLO [2.2.2] OCT-5-EN-2-YL
  申请人：Abele Stefan

  公开号：US20110263667A1

  公开（公告）日：2011-10-27

  The invention relates to crystalline salts of isobutyric acid (1R*,2R*,4R*)-2-(2-[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester, processes for the preparation thereof, pharmaceutical compositions containing said crystalline salts, and their use as medicaments, especially as calcium channel blockers.

  本发明涉及异丁酸晶体盐（1R*，2R*，4R*）-2-（2-[3-（4,7-二甲氧基-1H-苯并咪唑-2-基）-丙基]-甲基氨基}-乙基）-5-苯基-双环[2.2.2]辛-5-烯-2-基酯，其制备方法，含有所述晶体盐的制药组合物及其作为药物的用途，特别是作为钙通道阻滞剂。
• Salts of isobutyric acid (1 R*, 2R*, 4R*)-2-(2-{[3-(4,7-dimethoxy-1 H-benzoimidazol-2-yl)-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester
  申请人：Abele Stefan

  公开号：US08492555B2

  公开（公告）日：2013-07-23

  The invention relates to crystalline salts of isobutyric acid (1R*,2R*,4R*)-2-(2-[3-(4,7 -dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester, processes for the preparation thereof, pharmaceutical compositions containing said crystalline salts, and their use as medicaments, especially as calcium channel blockers.

  本发明涉及异丁酸晶体盐[(1R*，2R*，4R*)-2-(2-[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基氨基}-乙基)-5-苯基-双环[2.2.2]辛-5-烯-2-基]酯，该盐的制备方法，含有所述晶体盐的制药组合物以及其作为药物的用途，特别是作为钙通道阻滞剂。
• SALTS OF ISOBUTYRIC ACID (1 R*, 2R*, 4R* ) -2- (2-{ [3- (4, 7-DIMETH0XY-1 H-BENZOIMIDAZOL-2-YL) -PROPYL]-METHYL-AMINO } -ETHYL) -5-PHENYL-BICYCLO [2.2.2]OCT-5- EN- 2 -YL
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2344461A1

  公开（公告）日：2011-07-20