α-cyano-β-(2-bromo-5-methoxyphenyl)propionic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: α-cyano-β-(2-bromo-5-methoxyphenyl)propionic acid
• 英文别名: α-cyano-(2-bromo-5-methoxyphenyl)-propanoic acid；α-Cyano-2-brom-4-methoxyhydrozimtsaeure；α-Cyano-β-(2-brom-5-methoxyphenyl)propionsaeure；3-(2-bromo-5-methoxyphenyl)-2-cyanopropanoic acid；3-(2-Bromo-5-methoxyphenyl)-2-cyanopropanoic acid
• 化学式: C₁₁H₁₀BrNO₃
• 分子量: 284.109
• InChiKey: LTFCGZVQDDYBGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  70.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  α-cyano-β-(2-bromo-5-methoxyphenyl)propionic acid 在 aluminum (III) chloride 、 正十二烷基甲基硫醚 、 氨 、 sodium amide 作用下， 以 N,N-二甲基乙酰胺 、 甲苯 为溶剂， 反应 6.0h， 生成 3-羟基双环[4.2.0]辛-1,3,5-三烯-7-甲腈
  参考文献：
  名称：

  Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

  摘要：

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

  DOI：

  10.1021/jm2012968
• 作为产物：
  描述：

  α-cyano-(2-bromo-5-methoxy)cinnamic acid 在 甲醇 、 sodium tetrahydroborate 、 碳酸氢钠 作用下， 以99 %的产率得到α-cyano-β-(2-bromo-5-methoxyphenyl)propionic acid
  参考文献：
  名称：

  非对映体 8-氟-ABC-类固醇构建块的合成

  摘要：

  迄今为止，在 8 位具有氟取代基的两个非对映异构体 ABC 构建块在收敛合成中制备，具有八个线性步骤，来自 6-chlorohex-1-ene 和苯并环丁烯衍生物。关键步骤是邻醌二甲烷与含氟 α,β-不饱和酮的分子内 Diels-Alder 反应。

  DOI：

  10.1002/ejoc.202300206

文献信息

• Trehan, I. R.; Singh, N. P.; Jain, Vinay K., Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1995, vol. 34, # 6, p. 484 - 486
  作者：Trehan, I. R.、Singh, N. P.、Jain, Vinay K.

  DOI：——

  日期：——
• Studies on the syntheses of heterocyclic compounds. 675. A facile regiospecific and stereocontrolled synthesis of a diterpene alkaloid intermediate from benzocyclobutenes
  作者：Tetsuji Kametani、Yasuyuki Kato、Toshio Honda、Keiichiro Fukumoto

  DOI：10.1021/ja00441a050

  日期：1976.12
• Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists
  作者：Nobuyuki Negoro、Shinobu Sasaki、Masahiro Ito、Shuji Kitamura、Yoshiyuki Tsujihata、Ryo Ito、Masami Suzuki、Koji Takeuchi、Nobuhiro Suzuki、Junichi Miyazaki、Takashi Santou、Tomoyuki Odani、Naoyuki Kanzaki、Miyuki Funami、Toshimasa Tanaka、Tsuneo Yasuma、Yu Momose

  DOI：10.1021/jm2012968

  日期：2012.2.23

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
• Synthesis of Diastereomeric 8‐Fluoro‐ABC‐Steroid Building Blocks
  作者：Michael Essers、Günter Haufe

  DOI：10.1002/ejoc.202300206

  日期：——

  Two diastereomeric ABC-building blocks for hitherto widely unknown steroids with a fluorine substituent in 8-position were prepared in a convergent synthesis with eight linear steps from 6-chlorohex-1-ene and a benzocyclobutene derivative. Key step was an intramolecular Diels–Alder reaction of an o-quinodimethane with a fluorine-containing α,β-unsaturated ketone.

  迄今为止，在 8 位具有氟取代基的两个非对映异构体 ABC 构建块在收敛合成中制备，具有八个线性步骤，来自 6-chlorohex-1-ene 和苯并环丁烯衍生物。关键步骤是邻醌二甲烷与含氟 α,β-不饱和酮的分子内 Diels-Alder 反应。