(3R,4S,5S)-N-tert-butyloxycarbonyl-4-hydroxypiperidine-3,5-dicarboxylic acid 3-methyl ester | 309918-17-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3R,4S,5S)-N-tert-butyloxycarbonyl-4-hydroxypiperidine-3,5-dicarboxylic acid 3-methyl ester
• 英文别名: (3S,4S,5R)-1-(tert-butoxycarbonyl)-4-hydroxy-5-(methoxycarbonyl)piperidine-3-carboxylic acid；(3R,4S,5S)-1-(tert-butyloxycarbonyl)-4-hydroxypiperidine-3,5-dicarboxylic acid 3-methyl ester；(3S,4S,5R)-4-hydroxy-5-methoxycarbonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid
• CAS: 309918-17-0
• 化学式: C₁₃H₂₁NO₇
• 分子量: 303.312
• InChiKey: YBTXOKQDZOEALD-YIZRAAEISA-N

物化性质

• 沸点：
  453.4±45.0 °C(Predicted)
• 密度：
  1.309±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,4S,5S)-N-tert-butyloxycarbonyl-4-hydroxypiperidine-3,5-dicarboxylic acid 3-methyl ester 在 lithium hydroxide 、 硼烷四氢呋喃络合物 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 23.0h， 生成 (3R,4S,5R)-N-tert-butyloxycarbonyl-4-hydroxy-5-hydroxymethyl-4,5'-O-isopropylidene-piperidine-3-carboxylic acid
  参考文献：
  名称：

  Chemoenzymatic Synthesis of Isogalactofagomine

  摘要：

  A new chemoenzymatic synthesis of optically pure isogalactofagomine 2 starting from achiral starting materials is presented. Dimethyl 4-hydroxypyridine-3,5-dicarboxylate (7) was synthesized and converted to the corresponding saturated piperidine 8. Then the key step of the synthesis was carried out: Lipase M catalyzed hydrolysis of the prochiral diester 8 to cause formation of an asymmetric monoacid with at least 98% enantiomeric excess. Reduction of the acid, saponification of the remaining ester, and radical iododecarboxylation gave an iodide that after substitution with silver trifluoroacetate and hydrolysis gave 2.

  DOI：

  10.1021/jo000699r
• 作为产物：
  描述：

  (3,4-cis-4,5-cis)-4-hydroxypiperidine-3,5-dicarboxylic acid dimethyl ester hydroacetate 在 Mucor javanicus lipase 、 三乙胺 作用下， 以 aq. phosphate buffer 、 二氯甲烷 为溶剂， 反应 144.0h， 生成 (3R,4S,5S)-N-tert-butyloxycarbonyl-4-hydroxypiperidine-3,5-dicarboxylic acid 3-methyl ester
  参考文献：
  名称：

  Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

  摘要：

  A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

  DOI：

  10.1021/ml500137b

文献信息

• ORGANIC COMPOUNDS
  申请人：Yokokawa Fumiaki

  公开号：US20080319018A1

  公开（公告）日：2008-12-25

  The present invention relates to a compound of the formula I wherein R1, R2, R3, R4 and R5 are as defined in the specification, for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (=disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations a compound of that class; a method of treatment comprising administering a compound of that class and a method for its manufacture.

  本发明涉及一种具有以下公式I的化合物，其中R1、R2、R3、R4和R5如规范中所定义，用于诊断和治疗温血动物，特别是用于治疗依赖肾素活性的疾病；该类化合物用于制备用于治疗依赖肾素活性疾病的药物配方；该类化合物用于治疗依赖肾素活性的疾病；该类化合物的药物配方；包括给予该类化合物的治疗方法以及其制造方法。
• Organic compounds
  申请人：Yokokawa Fumiaki

  公开号：US08383650B2

  公开（公告）日：2013-02-26

  The present invention relates to a compound of the formula I wherein R1, R2, R3, R4 and R5 are as defined in the specification, for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (=disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations a compound of that class; a method of treatment comprising administering a compound of that class and a method for its manufacture.

  本发明涉及一种式I的化合物，其中R1、R2、R3、R4和R5如规范中所定义，用于诊断和治疗温血动物，特别是用于治疗依赖于肾素活性的疾病（=紊乱）；该类化合物用于制备用于治疗依赖于肾素活性的疾病的制剂；该类化合物用于治疗依赖于肾素活性的疾病；该类化合物的制剂；包括给予该类化合物的治疗方法和其制造方法。
• Organic Compounds
  申请人：Ehara Takeru

  公开号：US20090192148A1

  公开（公告）日：2009-07-30

  The invention relates to 3,5-substituted piperidine compounds, these compounds for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (=disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations comprising a 3,5-substituted piperidine compound, and/or a method of treatment comprising administering a 3,5-substituted piperidine compound, a method for the manufacture of a 3,5-substituted piperidine compound, and novel intermediates and partial steps for its synthesis. The compounds have the formula I′ wherein R1, R2, T, R3 and R4 areas defined in the specification.

  本发明涉及3,5-取代哌啶化合物，这些化合物用于诊断和治疗温血动物，特别是用于治疗依赖肾素活性的疾病（=失调）；该类化合物用于制备治疗依赖肾素活性疾病的制剂；该类化合物用于治疗依赖肾素活性的疾病；包括3,5-取代哌啶化合物的制药配方和/或包括给予3,5-取代哌啶化合物的治疗方法，以及制造3,5-取代哌啶化合物的新型中间体和部分合成步骤。该化合物的式子为I'，其中R1、R2、T、R3和R4在规范中有定义。
• Development of a Total Telescoped Synthesis of a Renin Inhibitor Containing 3,4,5-Substituted Piperidine with Sterically Hindered Amide Bonds
  作者：Wen-Chung Shieh、Zhengming Du、Hongyong Kim、Yugang Liu、Mahavir Prashad

  DOI：10.1021/op500116w

  日期：2014.11.21

  telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-controlled amidation protocol using Ghosez’s reagent in the presence of a mild acid scavenger for the formation of the first sterically hindered amide bond;

  描述了用于通过五步合成路线制造包含3,4,5-取代的哌啶的具有空间位阻酰胺键的肾素抑制剂的望远镜式合成。这种可扩展的合成方法的重点包括：（1）在温和的除酸剂存在下，使用Ghosez试剂进行副产物控制的酰胺化方案，以形成第一个空间位阻酰胺键。（2）位阻酯的化学选择性水解；（3）利用可溶的碳二亚胺导致第二个空间位阻酰胺键的有效酰胺化反应；（4）过滤最终药物的富马酸盐，这是整个合成过程中唯一必要的分离步骤。无需隔离任何中间体，这种伸缩式过程可以节省设备的使用，消耗更少的溶剂，并最大程度地减少了工艺废物的产生，能耗，人员暴露和环境影响。它提供了千克数量的高质量活性药物成分。
• 3 , 5-substitued piperidine compounds as renin inhibitors
  申请人：Novartis AG

  公开号：EP2420491A1

  公开（公告）日：2012-02-22

  The invention relates to 3,5-substituted piperidine compounds, these compounds for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (= disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations comprising a 3,5-substituted piperidine compound, and/or a method of treatment comprising administering a 3,5-substituted piperidine compound, a method for the manufacture of a 3, 5-substituted piperidine compound, and novel intermediates and partial steps for its synthesis. The compounds (which can also be present as salts) have the formula I' wherein R1, R2, T, R3, R4, R7 and R8 are as defined in the specification and R6 is OH.

  本发明涉及3,5-取代的哌啶化合物，这些化合物用于温血动物的诊断和治疗，特别是用于治疗依赖于肾素活性的疾病（=紊乱）；使用该类化合物制备药物制剂，用于治疗依赖于肾素活性的疾病；该类化合物在治疗依赖于肾素活性的疾病中的用途；包含 3,5-取代的哌啶化合物的药物制剂，和/或包括施用 3,5-取代的哌啶化合物的治疗方法，3,5-取代的哌啶化合物的制造方法，及其合成的新型中间体和部分步骤。 这些化合物（也可以以盐的形式存在）具有式 I' 其中 R1、R2、T、R3、R4、R7 和 R8 如说明书中所定义，R6 为 OH。