(1S,2S,4S,2'S)-(4-butylcarbamoyl-2-hydroxy-1-{2'-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl}-5-methylhexyl)carbamic acid tert-butyl ester | 173337-63-8

• 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: (1S,2S,4S,2'S)-(4-butylcarbamoyl-2-hydroxy-1-{2'-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl}-5-methylhexyl)carbamic acid tert-butyl ester
• 英文别名: 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (N-butyl) amide hydrochloride；tert-butyl N-[(3S,5S,6S,8S)-8-(butylcarbamoyl)-6-hydroxy-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-2,9-dimethyldecan-5-yl]carbamate
• CAS: 173337-63-8
• 化学式: C₃₄H₆₀N₂O₇
• 分子量: 608.86
• InChiKey: PWEMXAOXROEUNQ-DZUOILHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  43
• 可旋转键数：
  22
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1S,2S,4S,2'S)-(4-butylcarbamoyl-2-hydroxy-1-{2'-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl}-5-methylhexyl)carbamic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 以96%的产率得到5(S)-amino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (N-butyl) amide hydrochloride
  参考文献：
  名称：

  Structural Modification of the P2‘ Position of 2,7-Dialkyl-Substituted 5(S)-Amino-4(S)-hydroxy-8-phenyl-octanecarboxamides:  The Discovery of Aliskiren, a Potent Nonpeptide Human Renin Inhibitor Active after Once Daily Dosing in Marmosets

  摘要：

  Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension.

  DOI：

  10.1021/jm070316i
• 作为产物：
  描述：

  [(1S,3S)-3-[[4-甲氧基-3-(3-甲氧基丙氧基)苯基]甲基]-4-甲基-1-[(2S)-四氢-5-氧代-2-呋喃基]戊基]氨基甲酸苄酯 在 五氯化磷 、 三甲基铝 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 92.5h， 生成 (1S,2S,4S,2'S)-(4-butylcarbamoyl-2-hydroxy-1-{2'-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl}-5-methylhexyl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  强大的肾素抑制剂阿利吉仑的正式全合成：SmI 2促进的酰基样自由基偶联剂的应用

  摘要：

  公开了有效的肾素抑制剂阿利吉仑的正式全合成，其利用了由该实验室最近开发的用于制备基于羟乙烯等排酯的一类蛋白酶抑制剂的替代偶联策略。通过SMI硫酯衍生物表示阿利吉仑碳骨架的C5-C9片段的氨基酸的进行了碳链延长2促进的自由基加成到Ñ丙烯酸丁酯。具有正确的相对构型的C 3-异丙基的引入是通过伴随内酯化的立体选择性还原获得的酮，然后与丙酮进行醛醇缩合反应而完成的。进一步的官能团和保护基团的操作最终使阿利吉仑从相应的受完全保护的非天然氨基酸开始进行正式的全合成，最终完成了10个步骤。

  DOI：

  10.1021/jo060296c

文献信息

• Structural Modification of the P2‘ Position of 2,7-Dialkyl-Substituted 5(<i>S</i>)-Amino-4(<i>S</i>)-hydroxy-8-phenyl-octanecarboxamides:  The Discovery of Aliskiren, a Potent Nonpeptide Human Renin Inhibitor Active after Once Daily Dosing in Marmosets
  作者：Jürgen Maibaum、Stefan Stutz、Richard Göschke、Pascal Rigollier、Yasuchika Yamaguchi、Frédéric Cumin、Joseph Rahuel、Hans-Peter Baum、Nissim-Claude Cohen、Christian R. Schnell、Walter Fuhrer、Markus G. Gruetter、Walter Schilling、Jeanette M. Wood

  DOI：10.1021/jm070316i

  日期：2007.10.1

  Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension.
• Formal Total Synthesis of the Potent Renin Inhibitor Aliskiren:  Application of a SmI₂-Promoted Acyl-like Radical Coupling
  作者：Karl B. Lindsay、Troels Skrydstrup

  DOI：10.1021/jo060296c

  日期：2006.6.1

  A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5−C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted

  公开了有效的肾素抑制剂阿利吉仑的正式全合成，其利用了由该实验室最近开发的用于制备基于羟乙烯等排酯的一类蛋白酶抑制剂的替代偶联策略。通过SMI硫酯衍生物表示阿利吉仑碳骨架的C5-C9片段的氨基酸的进行了碳链延长2促进的自由基加成到Ñ丙烯酸丁酯。具有正确的相对构型的C 3-异丙基的引入是通过伴随内酯化的立体选择性还原获得的酮，然后与丙酮进行醛醇缩合反应而完成的。进一步的官能团和保护基团的操作最终使阿利吉仑从相应的受完全保护的非天然氨基酸开始进行正式的全合成，最终完成了10个步骤。