[S(R*,R*)]-1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylicacid, methyl ester | 111581-88-5

• 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: [S(R*,R*)]-1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylicacid, methyl ester
• 英文别名: (S)-1-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-phenylpropionyl]-1,2,3,4-tetrahydropyridine-2-carboxylic acid methyl ester；methyl (2S)-1-[(2S)-2-(1,3-dioxoisoindol-2-yl)-3-phenylpropanoyl]-3,4-dihydro-2H-pyridine-2-carboxylate
• CAS: 111581-88-5
• 化学式: C₂₄H₂₂N₂O₅
• 分子量: 418.449
• InChiKey: TZXZGUGWPWXOOE-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  84
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [S(R*,R*)]-1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylicacid, methyl ester 在 三氟甲磺酸 、 1,8-双二甲氨基萘 、 肼 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 24.0h， 生成 benzhydryl (4S,7S,12bR)-7-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-6-oxo-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylate
  参考文献：
  名称：

  An acyl-iminium ion cyclization route to a novel conformationally restricted dipeptide mimic: applications to angiotensin-converting enzyme inhibition

  摘要：

  DOI：

  10.1021/ja00259a068
• 作为产物：
  描述：

  苯酐 在 N-甲基吗啉 、 草酰氯 、 magnesium sulfate 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙酸乙酯 、 甲苯 、 乙腈 为溶剂， 反应 36.67h， 生成 [S(R*,R*)]-1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylicacid, methyl ester
  参考文献：
  名称：

  Process Development in the Synthesis of the ACE Intermediate MDL 28,726

  摘要：

  MDL 28,726 is a key intermediate in the synthesis of the ACE inhibitors MDL 27,210A and MDL 100,240, An efficient nine-step synthesis of this tricyclic acid, which has three chiral centers, was developed beginning with 3,4-dihydro-2H-pyran. A key step in the synthesis features an enzyme-catalyzed resolution of the lithium salt of the N-trifluoroacetamide of (R,S)-6-hydroxynorleucine. All of the steps were optimized and completed in reactor equipment using environmentally acceptable processes. Process development of this route is described.

  DOI：

  10.1021/op970125x

文献信息

• N-formyl hydroxylamine containing compounds useful as ACE inhibitors and/or NEP inhibitors
  申请人：Bristol-Myers Squibb Company

  公开号：US06777550B1

  公开（公告）日：2004-08-17

  N-formyl hydroxylamines are provided which have the structure wherein R is H, alkyl, alkenyl, aryl-(CH2)p—, heteroaryl-(CH2)p— or cycloheteroalkyl-(CH2)p— R1 is H or COR2 where R2 is alkyl, aryl-(CH2)p—, cycloheteroalkyl-(CH2)p—, heteroaryl-(CH2)p—, alkoxy or cycloalkyl-(CH2)p—, p is 0 to 8, and A is a dipeptide derived from an amino acid or is a conformationally restricted dipeptide mimic. The above compounds are useful in treating hypertension congestive heart failure, renal failure, and hepatic cirrhosis.

  提供了具有以下结构的N-甲酰羟胺，其中R为H，烷基，烯基，芳基-(CH2)p—，杂芳基-(CH2)p—或环杂芳基-(CH2)p—；R1为H或COR2，其中R2为烷基，芳基-(CH2)p—，环杂芳基-(CH2)p—，杂芳基-(CH2)p—，烷氧基或环烷基-(CH2)p—；p为0至8，A为来源于氨基酸的二肽或是具有构象限制的二肽模拟物。上述化合物在治疗高血压、充血性心力衰竭、肾功能衰竭和肝硬化方面具有用途。
• [EN] HYDROFORMYLATION PROCESS FOR PHARMACEUTICAL INTERMEDIATE<br/>[FR] PROCÉDÉ D'HYDROFORMYLATION D'INTERMÉDIAIRES PHARMACEUTIQUES
  申请人：DOW GLOBAL TECHNOLOGIES INC

  公开号：WO2005110986A1

  公开（公告）日：2005-11-24

  The invention relates to an improved process for the preparation of an advanced synthetic intermediate of ACE inhibitors. In one aspect, the present invention is based on a novel process for the preparation of an aldehyde of formula (I), wherein (N)PrG is a protected amino group, R is an alkyl or aralkyl group and X1-4 are each independently H or a non-reacting substituent, which comprises hydroformylation of an α-olefin of formula (II), by reaction with syngas (CO/H2) in the presence of, as catalyst, a group VIII transition metal complex of a phosphorus-containing ligand. Aldehyde (I), the product of linear hydroformylation, is formed in preference to aldehyde (III). In another aspect of the invention, α-olefin (II) is a novel composition. The process to convert (II) to (I) enables an efficient manufacturing route to MDL 28,726 and analogues.

  该发明涉及一种改进的制备ACE抑制剂高级合成中间体的工艺。在一个方面，本发明基于一种新颖的制备式(I)醛的工艺，其中(N)PrG是保护的氨基团，R是烷基或芳基烷基团，X1-4分别独立地是H或非反应取代基，包括通过与合成气(CO/H2)在磷含配体的第VIII族过渡金属复合物的催化剂存在下，对式(II)的α-烯烃进行水甲醛化。醛(I)，线性水甲醛化的产物，优先形成醛(III)。在本发明的另一个方面，α-烯烃(II)是一种新型组合物。将(II)转化为(I)的工艺为MDL 28,726及类似物提供了一条高效的制造途径。
• HYDROFORMYLATION PROCESS FOR PHARMACEUTICAL INTERMEDIATE
  申请人：Daugs Edward D

  公开号：US20090247744A1

  公开（公告）日：2009-10-01

  The invention relates to an improved process for the preparation of an advanced synthetic intermediate of ACE inhibitors. In one aspect, the present invention is based on a novel process for the preparation of an aldehyde of formula (I), wherein (N) PrG is a protected amino group, R is an alkyl or aralkyl group and X 1-4 are each independently H or a non-reacting substituent, which comprises hydroformylation of an α-olefin of formula (II), by reaction with syngas (CO/H 2 ) in the presence of, as catalyst, a group VII transition metal complex of a phosphorus-containing ligand. Aldehyde (I), the product of linear hydroformylation, is formed in preference to aldehyde (III). In another aspect of the invention, α-olefin (II) is a novel composition. The process to convert (II) to (I) enables an efficient manufacturing route to MDL 28,726 and analogues.

  本发明涉及一种改进的制备ACE抑制剂先进合成中间体的过程。在一个方面，本发明基于一种新的制备式(I)的醛的过程，其中(N)PrG是保护的氨基团，R是烷基或芳基烷基团，X1-4是各自独立的H或不反应的取代基，包括通过与合成气(CO/H2)反应，在含有含磷配体的第VII族过渡金属配合物的催化剂存在下，对式(II)的α-烯烃进行加氢甲酰化。醛(I)是线性加氢甲酰化的产物，优先形成于醛(III)。在本发明的另一个方面，α-烯烃(II)是一种新的组合物。将(II)转化为(I)的过程实现了MDL 28,726和类似物的高效制造路线。
• Hydroformylation Process for Pharmaceutical Intermediate
  申请人：Daugs D. Edward

  公开号：US20080027218A1

  公开（公告）日：2008-01-31

  The invention relates to an improved process for the preparation of an advanced synthetic intermediate of ACE inhibitors. In one aspect, the present invention is based on a novel process for the preparation of an aldehyde of formula (I), wherein (N) PrG is a protected amino group, R is an alkyl or aralkyl group and X 1-4 are each independently H or a non-reacting substituent, which comprises hydroformylation of an α-olefin of formula (II), by reaction with syngas (CO/H 2 ) in the presence of, as catalyst, a group VIII transition metal complex of a phosphorus-containing ligand. Aldehyde (I), the product of linear hydroformylation, is formed in preference to aldehyde (III). In another aspect of the invention, α-olefin (II) is a novel composition. The process to convert (II) to (I) enables an efficient manufacturing route to MDL 28,726 and analogues.

  本发明涉及一种改进的制备ACE抑制剂的先进合成中间体的方法。在一方面，本发明基于一种新颖的制备式(I)醛的方法，其中（N）PrG是受保护的氨基基团，R是烷基或芳基烷基基团，X1-4分别独立地为H或非反应性取代基，包括通过与合成气（CO/H2）反应，在含有含磷配体的8族过渡金属配合物的催化剂存在下，对式(II)的α-烯烃进行氢甲酰化。线性氢甲酰化产物(I)的醛优先形成，而非醛(III)。在本发明的另一方面，α-烯烃(II)是一种新的组合物。将(II)转化为(I)的过程使MDL 28,726和类似物的有效制造路线成为可能。
• Design, Synthesis, and Evaluation of Tricyclic, Conformationally Constrained Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases
  作者：Bin Zhang、Zaneta Nikolovska-Coleska、Yan Zhang、Longchuan Bai、Su Qiu、Chao-Yie Yang、Haiying Sun、Shaomeng Wang、Yikang Wu

  DOI：10.1021/jm801146d

  日期：2008.12.11

  A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K-i of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC50 of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.