2-(R)-2-hydroxypentanedioic acid, 1-tert-butyl-5-benzyl ester | 914639-10-4

• 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: 2-(R)-2-hydroxypentanedioic acid, 1-tert-butyl-5-benzyl ester
• 英文别名: 5-benzyl 1-(tert-butyl) (R)-2-hydroxypentanedioate；2-(R)-2-hydroxy pentanedioic acid 1-t-butyl-5-benzyl ester；5-O-benzyl 1-O-tert-butyl (2R)-2-hydroxypentanedioate
• CAS: 914639-10-4
• 化学式: C₁₆H₂₂O₅
• 分子量: 294.348
• InChiKey: CNPUVTAXVGSDEH-CYBMUJFWSA-N

物化性质

• 沸点：
  407.5±35.0 °C(Predicted)
• 密度：
  1.135±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(R)-2-hydroxypentanedioic acid, 1-tert-butyl-5-benzyl ester 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 异丙醇 、 乙腈 为溶剂， 50.0 ℃ 、413.7 kPa 条件下， 反应 62.0h， 生成
  参考文献：
  名称：

  Enantiopure bifunctional chelators for copper radiopharmaceuticals – Does chirality matter in radiotracer design?

  摘要：

  It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.

  DOI：

  10.1016/j.ejmech.2014.04.071
• 作为产物：
  描述：

  D-谷氨酸 在 盐酸 、 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 、 potassium hydroxide 、 sodium nitrite 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 36.0h， 生成 2-(R)-2-hydroxypentanedioic acid, 1-tert-butyl-5-benzyl ester
  参考文献：
  名称：

  Enantiopure bifunctional chelators for copper radiopharmaceuticals – Does chirality matter in radiotracer design?

  摘要：

  It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.

  DOI：

  10.1016/j.ejmech.2014.04.071

文献信息

• Chemical exchange saturation transfer contrast agents
  申请人：Caravan D. Peter

  公开号：US20060275217A1

  公开（公告）日：2006-12-07

  Chelating ligands and metal chelates useful as CEST MR contrast agents are disclosed. The CEST agents can be used to evaluate blood volume changes in the heart and brain.

  螯合配体和金属螯合物作为CEST磁共振对比剂是有用的。CEST对比剂可用于评估心脏和大脑的血容量变化。
• Development of a Multigram Asymmetric Synthesis of 2-(<i>R</i>)-2-(4,7,10-Tris <i>tert</i>-Butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic Acid, 1-<i>tert</i>-Butyl Ester, (<i>R</i>)-<i>tert</i>-Bu₄-DOTAGA
  作者：Stuart G. Levy、Vincent Jacques、Kevin Li Zhou、Shirley Kalogeropoulos、Kelly Schumacher、John C. Amedio、Jonathan E. Scherer、Steven R. Witowski、Richard Lombardy、Karsten Koppetsch

  DOI：10.1021/op8002932

  日期：2009.5.15

  A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-(S)-5-oxotetrahydrofuran-2-carboxylic acid, tert-butyl ester 8, the precursor to the

  手性四氮杂大环2-（R）-2-（4,7,10-三叔丁基丁基羧甲基-1,4,7,10-四氮杂环十二烷基-1-基）-戊二酸的多克不对称合成方法1 -叔丁基酯（（[R ）-叔-Bu 4 -DOTAGA，4）已经设计和展示。九步合成法改进了2-（S）-5-氧代四氢呋喃-2-羧酸叔丁酯8的合成，该酯是新型烷基化剂（S）-5-苄基1-叔丁基的前体2-（甲基磺酰氧基）戊二酸酯12，用于以高光学纯度将正交保护的手性谷氨酸臂引入1,4,7,10-四氮杂环十二烷（环）核。环烯衍生物（[R ）-吨-Bu 4 -DOTAGA，4，一种用于磁共振成像中的用途的关键中间体（MRI）的候选，以高化学（≥95％）和光（EE≥97％）纯度产生。开发的方法成功地应用于的千克规模的cGMP合成（- [R ） -吨-Bu 4 -DOTAGA。
• Optically pure and enriched isomers of chelating ligands and contrast agents
  申请人：Amedio C. John

  公开号：US20070244316A1

  公开（公告）日：2007-10-18

  Organic chelating ligands, organic chelating ligand precursors, and metal chelates are disclosed. Methods for synthesizing the same are also described, including methods for preparing optically-enriched or optically-pure compositions of the same.

  本发明公开了有机螯合配体、有机螯合配体前体和金属螯合物。还描述了合成它们的方法，包括制备光学富集或光学纯的相同组成的方法。
• US8048906B2
  申请人：——

  公开号：US8048906B2

  公开（公告）日：2011-11-01
• Enantiopure bifunctional chelators for copper radiopharmaceuticals – Does chirality matter in radiotracer design?
  作者：Ajay N. Singh、Marianna Dakanali、Guiyang Hao、Saleh Ramezani、Amit Kumar、Xiankai Sun

  DOI：10.1016/j.ejmech.2014.04.071

  日期：2014.6

  It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.