(1SR,2SR,5RS,6RS)-Ethyl N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1SR,2SR,5RS,6RS)-Ethyl N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate
• 英文别名: 2-O-benzyl 3-O-ethyl (3S,3aS,6R,6aR)-6-hydroxy-6-methyl-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrole-2,3-dicarboxylate
• 化学式: C₁₉H₂₅NO₅
• 分子量: 347.411
• InChiKey: FUZTWEQRKXRVCL-IUVQAAGXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1SR,2SR,5RS,6RS)-Ethyl N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate 在 ruthenium(IV) oxide 、 sodium hydroxide 、 sodium periodate 、 三氟化硼乙醚 、 四氯化钛 、 potassium carbonate 、 锌 作用下， 以 四氢呋喃 、 四氯化碳 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 135.0h， 生成 (+/-)-α-kainic acid
  参考文献：
  名称：

  A Concise, Stereocontrolled Thiazolium Ylide Approach to Kainic Acid

  摘要：

  Racemic alpha-kainic acid (1) has been prepared from (1SR,2SR,5RS)-ethyl (N-(benzyloxycarbonyl)3-aza-6-oxobicyclo[3.3.0] octane-2-carboxylate (11) in ca. 16% overall yield via a concise six-step synthetic sequence. Compound 11 is prepared pn a large scale in 50% yield via the [3 + 2] cycloaddition of thiazolium ylide 9 and 2-cyclopentenone, which provides the requisite 2,3-trans, 3,4-cis stereochemical array about the trisubstituted pyrrolidine nucleus in 1. Chemoselective addition of the one-to-one adduct of MeLi and TiCl4 to the ketone functionality in 11 followed by dehydration, oxidative ring opening, and nonbasic methylenation of the stereochemically labile C4 acetate moiety with CH2I2-Zn-TiCl4 affords the fully protected penultimate intermediate 17 which is exhaustively hydrolyzed to provide 1. This represents a highly efficient and stereocontrolled preparation of (+/-)-alpha-kainic acid.

  DOI：

  10.1021/jo00089a022
• 作为产物：
  描述：

  氯甲酸苄酯 在 sodium hydroxide 、 四氯化钛 作用下， 以 乙醚 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 3.0h， 生成 (1SR,2SR,5RS,6RS)-Ethyl N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate
  参考文献：
  名称：

  A Concise, Stereocontrolled Thiazolium Ylide Approach to Kainic Acid

  摘要：

  Racemic alpha-kainic acid (1) has been prepared from (1SR,2SR,5RS)-ethyl (N-(benzyloxycarbonyl)3-aza-6-oxobicyclo[3.3.0] octane-2-carboxylate (11) in ca. 16% overall yield via a concise six-step synthetic sequence. Compound 11 is prepared pn a large scale in 50% yield via the [3 + 2] cycloaddition of thiazolium ylide 9 and 2-cyclopentenone, which provides the requisite 2,3-trans, 3,4-cis stereochemical array about the trisubstituted pyrrolidine nucleus in 1. Chemoselective addition of the one-to-one adduct of MeLi and TiCl4 to the ketone functionality in 11 followed by dehydration, oxidative ring opening, and nonbasic methylenation of the stereochemically labile C4 acetate moiety with CH2I2-Zn-TiCl4 affords the fully protected penultimate intermediate 17 which is exhaustively hydrolyzed to provide 1. This represents a highly efficient and stereocontrolled preparation of (+/-)-alpha-kainic acid.

  DOI：

  10.1021/jo00089a022

文献信息

• Peptidomimetic protease inhibitors
  申请人：Babine Robert Edward

  公开号：US20100137583A1

  公开（公告）日：2010-06-03

  The present invention relates to peptidomimetic compounds useful as protease inhibitors, particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective processes to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.

  本发明涉及用作蛋白酶抑制剂的肽类模拟化合物，特别是丝氨酸蛋白酶抑制剂，更特别是丙型肝炎NS3蛋白酶抑制剂；其中间体；它们的制备，包括新的对中间体的立体选择性过程。本发明还涉及制药组合物和使用该化合物抑制HCV蛋白酶或治疗患有HCV感染或与感染相关的生理状况的患者的方法。还提供了药物组合物，其中包括除一种或多种HCV丝氨酸蛋白酶抑制剂外，还包括一种或多种表现出抗HCV活性的干扰素和/或一种或多种具有抗HCV活性的化合物和药学可接受载体，并使用该组合物治疗或预防患者的HCV感染的方法。本发明还涉及用于治疗或预防患者HCV感染的工具包或药品包。
• PEPTIDOMIMETIC PROTEASE INHIBITORS
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20140294763A1

  公开（公告）日：2014-10-02

  The present invention relates to peptidomimetic compounds useful as protease inhibitors, particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective processes to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.

  本发明涉及肽类似物化合物，可用作蛋白酶抑制剂，特别是作为丝氨酸蛋白酶抑制剂，更特别是作为丙型肝炎NS3蛋白酶抑制剂；其中间体；它们的制备，包括新的立体选择性过程到中间体。该发明还涉及制药组合物和使用该化合物抑制HCV蛋白酶或治疗患有HCV感染或与感染相关的生理状况的患者的方法。还提供了制药组合物，包括除一个或多个HCV丝氨酸蛋白酶抑制剂外，还有一个或多个表现出抗HCV活性的干扰素和/或一个或多个具有抗HCV活性的化合物和药学上可接受的载体，并使用该组合物治疗或预防患者的HCV感染的方法。本发明还涉及用于治疗或预防患者HCV感染的套件或药物包装。
• Stereocontrolled Synthesis of 4-Substituted (±)-Kainic Acids
  作者：Iván Collado、Jesús Ezquerra、Ana I. Mateo、Almudena Rubio

  DOI：10.1021/jo972123g

  日期：1998.3.1

  Racemic 4-substituted kainic acids 4a,b have been synthesized from ethyl (1SR, 2SR, 5RS, 6RS)-N-(benzyloxycarbonyl)-3-aza-6-hydroxy-6-methylbicyclo[3.3.0]octane-2-carboxylate (7) after its transformation in the pyroglutamate derivative 6. The key step in the synthesis has been the regioselective alkylation of 6 to obtain 11a,b, without compromising the stereogenic integrity of the potentially labile C-2 center. The elaboration of the C-3 and C-4 substituents of kainic acid over 11 was achieved after double bond isomerization of 11, oxidative double bond cleavage of 5, and chemoselective aldehyde reduction of 16 followed by Wittig olefination reaction of 17 and final alcohol oxidation and hydrolysis over 18 to the corresponding 4-methyl kainic acid 4a and 4-benzyl kainic acid 4b. The relatively small changes introduced in the structure of kainic acid 1 have been found to lead to a loss of affinity for kainate receptors.
• US7820671B2
  申请人：——

  公开号：US7820671B2

  公开（公告）日：2010-10-26
• US8252923B2
  申请人：——

  公开号：US8252923B2

  公开（公告）日：2012-08-28