(S)-2-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-hexanoic acid methyl ester | 142589-43-3

• 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)-2-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-hexanoic acid methyl ester
• 英文别名: methyl (2S)-2-[[(2S)-2-(1,3-dioxoisoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate
• CAS: 142589-43-3
• 化学式: C₂₄H₂₄N₂O₆
• 分子量: 436.464
• InChiKey: ZPIHQVOGLXTHKO-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  32
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-2-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-hexanoic acid methyl ester 在 甲烷磺酸 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 以51%的产率得到[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：

  [EN] HYDROFORMYLATION PROCESS FOR PHARMACEUTICAL INTERMEDIATE
  [FR] PROCÉDÉ D'HYDROFORMYLATION D'INTERMÉDIAIRES PHARMACEUTIQUES

  摘要：

  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。

  公开号：

  WO2005110986A1
• 作为产物：
  描述：

  (S)-2-amino-6-hydroxy-hexanoic acid methyl ester 在 N-甲基吗啉 、 草酰氯 、 二甲基亚砜 作用下， 以 二氯甲烷 、 乙酸乙酯 、 乙腈 为溶剂， 反应 0.17h， 生成 (S)-2-[(S)-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-hexanoic acid 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。
• Process Development in the Synthesis of the ACE Intermediate MDL 28,726
  作者：Stephen W. Horgan、David W. Burkhouse、Robert J. Cregge、David W. Freund、Michael LeTourneau、Alexey Margolin、Mark E. Webster、Daniel R. Henton、Kathy P. Barton、Robert C. Clouse、Michael A. DesJardin、Richard E. Donaldson、Neal J. Fetner、Christian T. Goralski、Gerald P. Heinrich、John F. Hoops、Robert T. Keaten、J. Russell McConnell、Mark A. Nitz、Sandra K. Stolz-Dunn

  DOI：10.1021/op970125x

  日期：1999.7.1

  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.