ethyl 2-benzyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 2-benzyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate
• 英文别名: ethyl 2-benzyl-1,3-dioxo-4H-pyrrolo[1,2-a]pyrazine-4-carboxylate
• 化学式: C₁₇H₁₆N₂O₄
• 分子量: 312.325
• InChiKey: WPCOXABVFBBABH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  68.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 2-benzyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate 在 ammonium hydroxide 、 氯化亚砜 、 sodium hydride 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 8.5h， 生成 2-Benzyl-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Novel, Highly Potent Aldose Reductase Inhibitors:  (R)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners

  摘要：

  A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a][1,2a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)enantiomer 44 (SX-3202): From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

  DOI：

  10.1021/jm9802968
• 作为产物：
  描述：

  2-(三氯乙酰)吡咯 在 四丁基碘化铵 、 sodium hydride 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.67h， 生成 ethyl 2-benzyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylate
  参考文献：
  名称：

  （2-苄基-1,2,3,4-四氢吡咯并[1,2-a]吡嗪）-4-甲醇的合成方法

  摘要：

  本发明涉及一种（2‑苄基‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪）‑4‑甲醇的合成方法。解决既知方法合成操作困难，原料昂贵的技术问题。本发明以吡咯与三氯乙酰氯反应得到2‑（三氯乙酰）吡咯；其在冰浴下加入氢化钠，后与溴乙酸甲酯反应得到2‑(2‑(2,2,2‑三氯乙酰基)‑1‑吡咯基)‑乙酸甲酯；然后将它和三乙胺溶于二甲基甲酰胺，滴加苄胺室温搅拌过夜即得2‑苄基‑吡咯并[1,2‑a]吡嗪‑1,3(2H,4H)‑二酮；而后将1,3‑二甲基‑3,4,5,6‑四氢‑2‑嘧啶酮溶于四氢呋喃加入六甲基二硅基胺基锂后，滴加2‑苄基‑吡咯并[1,2‑a]吡嗪‑1,3(2H,4H)‑二酮的四氢呋喃溶液，加入氰基甲酸乙酯得到2‑苄基‑1,3‑二氧‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪‑4‑甲酸乙酯；最后用硼烷四氢呋喃溶液将2‑苄基‑1,3‑二氧‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪‑4‑甲酸乙酯的二羰基和酯基还原得到产品。

  公开号：

  CN106928234A

文献信息

• Novel, Highly Potent Aldose Reductase Inhibitors:  (<i>R</i>)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-<i>a</i>]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners
  作者：Toshiyuki Negoro、Makoto Murata、Shozo Ueda、Buichi Fujitani、Yoshiyuki Ono、Akemi Kuromiya、Masanobu Komiya、Kenji Suzuki、Jun-ichi Matsumoto

  DOI：10.1021/jm9802968

  日期：1998.10.1

  A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo- [1,2-a][1,2a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)enantiomer 44 (SX-3202): From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.
• （2-苄基-1,2,3,4-四氢吡咯并[1,2-a]吡嗪）-4-甲醇的合成方法
  申请人：上海合全药业股份有限公司

  公开号：CN106928234A

  公开（公告）日：2017-07-07

  本发明涉及一种（2‑苄基‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪）‑4‑甲醇的合成方法。解决既知方法合成操作困难，原料昂贵的技术问题。本发明以吡咯与三氯乙酰氯反应得到2‑（三氯乙酰）吡咯；其在冰浴下加入氢化钠，后与溴乙酸甲酯反应得到2‑(2‑(2,2,2‑三氯乙酰基)‑1‑吡咯基)‑乙酸甲酯；然后将它和三乙胺溶于二甲基甲酰胺，滴加苄胺室温搅拌过夜即得2‑苄基‑吡咯并[1,2‑a]吡嗪‑1,3(2H,4H)‑二酮；而后将1,3‑二甲基‑3,4,5,6‑四氢‑2‑嘧啶酮溶于四氢呋喃加入六甲基二硅基胺基锂后，滴加2‑苄基‑吡咯并[1,2‑a]吡嗪‑1,3(2H,4H)‑二酮的四氢呋喃溶液，加入氰基甲酸乙酯得到2‑苄基‑1,3‑二氧‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪‑4‑甲酸乙酯；最后用硼烷四氢呋喃溶液将2‑苄基‑1,3‑二氧‑1,2,3,4‑四氢吡咯并[1,2‑a]吡嗪‑4‑甲酸乙酯的二羰基和酯基还原得到产品。