(2R,3S,4S,5R)-2,5-bis[N-(benzyloxycarbonyl)amino]-1,6-diphenyl-3,4-hexanediol | 153223-10-0

• 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: (2R,3S,4S,5R)-2,5-bis[N-(benzyloxycarbonyl)amino]-1,6-diphenyl-3,4-hexanediol
• 英文别名: (2R,3S,4S,5R)-2,5-bis-(N-Cbz-amino)-3,4-(dihydroxy)-1,6-diphenylhexane；benzyl N-[(2R,3S,4S,5R)-3,4-dihydroxy-1,6-diphenyl-5-(phenylmethoxycarbonylamino)hexan-2-yl]carbamate
• CAS: 153223-10-0
• 化学式: C₃₄H₃₆N₂O₆
• 分子量: 568.67
• InChiKey: VHZZMBIUMSGNBP-ZRTHHSRSSA-N

物化性质

• 沸点：
  792.4±60.0 °C(Predicted)
• 密度：
  1.242±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  42
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  117
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R,3S,4S,5R)-2,5-bis[N-(benzyloxycarbonyl)amino]-1,6-diphenyl-3,4-hexanediol 在 六羰基钨 、 20 % Pd(OH)2/C 、 碘 、 potassium carbonate 、 N,N-二异丙基乙胺 、 环己烯 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 24.0h， 生成 (4R,5S,6S,7R)-hexahydro-5,6-bis[2-(trimethylsilyl)ethoxymethoxy]-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
  参考文献：
  名称：

  官能化二胺二醇羰基化为环状脲：在DMP 450衍生物中的应用

  摘要：

  HIV蛋白酶抑制剂DMP 450的环状脲核心结构的合成已经通过W（CO）6 / I 2催化的二胺中间体的羰基化而实现。还检查了相关的官能化二胺羰基化为DMP 450核心结构的衍生物。选定的二胺二醇底物可通过催化羰基化转化为环状脲核心结构，而无需保护二醇的功能。

  DOI：

  10.1016/j.tet.2011.04.015
• 作为产物：
  描述：

  N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide 在 lithium aluminium tetrahydride 、 [VCl3(thf)3] 、 铜 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 (2R,3S,4S,5R)-2,5-bis[N-(benzyloxycarbonyl)amino]-1,6-diphenyl-3,4-hexanediol
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n

文献信息

• Stereoisomers of Cyclic Urea HIV-1 Protease Inhibitors:  Synthesis and Binding Affinities
  作者：Robert F. Kaltenbach、David A. Nugiel、Patrick Y. S. Lam、Ronald M. Klabe、Steven P. Seitz

  DOI：10.1021/jm980255b

  日期：1998.12.1

  We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino acid starting materials was used to prepare three isomers. Three additional isomers were prepared by synthetic routes

  我们已经合成了环状脲HIV-1蛋白酶抑制剂的立体异构体，以研究各种构型对结合亲和力的影响。使用四种不同的合成方法来制备所需的环状脲立体异构体。使用氨基酸起始原料的原始环状脲合成用于制备三种异构体。通过使用L-酒石酸和D-山梨糖醇作为手性原料的合成路线制备了三种另外的异构体。环状脲反式二醇的立体选择性羟基转化用于制备三种另外的异构体。共准备了10种可能的全部9种环状脲立体异构体，并描述了它们的结合亲和力。
• Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323
  作者：Michael E. Pierce、Gregory D. Harris、Qamrul Islam、Lilian A. Radesca、Louis Storace、Robert E. Waltermire、Ed Wat、Prabhakar K. Jadhav、George C. Emmett

  DOI：10.1021/jo951847u

  日期：1996.1.1

  DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to

  DMP 323是一种有效的HIV-1蛋白酶抑制剂，已经通过有效的立体选择性方法合成，适用于大规模制备。核心的C（2）对称二醇是由CBZ保护的D-苯丙氨酸的立体选择性频哪醇偶联合成的。明智地选择保护基团可以在温和条件下形成环状脲，增强了双烷基化的难度，并导致了无需色谱即可轻松纯化的中间体。另外，开发了一种单锅高产率方法，以从1，4-苯二甲醇制备烷基化剂4-[（（三苯基甲氧基）甲基]苄基氯。
• Nonpeptide Cyclic Cyanoguanidines as HIV-1 Protease Inhibitors:  Synthesis, Structure−Activity Relationships, and X-ray Crystal Structure Studies
  作者：Prabhakar K. Jadhav、Francis J. Woerner、Patrick Y. S. Lam、C. Nicholas Hodge、Charles J. Eyermann、Hon-Wah Man、Wayne F. Daneker、Lee T. Bacheler、Marlene M. Rayner、James L. Meek、Susan Erickson-Viitanen、David A. Jackson、Joseph C. Calabrese、Margaret Schadt、Chong-Hwan Chang

  DOI：10.1021/jm970524i

  日期：1998.4.1

  native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of

  天然HIV-1蛋白酶及其抑制剂与复合物的高分辨率X射线结构比较表明，酶瓣具有柔性。襟翼末端的运动可能高达7A。基于此观察结果，已设计，合成并评估了环状氰基胍作为HIV-1蛋白酶（PR）抑制剂。发现环状氰基胍是HIV-1蛋白酶的非常有效的抑制剂。与环状胍相比，环状氰基胍的选择是基于前者的碱性降低。具有环状氰基胍的HIV PR复合物的X射线结构研究表明，与环状脲类似，环状氰基胍也取代了独特的结构水分子。将环状氰基胍的结构-活性关系与相应的环状脲类似物的结构-活性关系进行了比较。使用高分辨率的X射线结构信息已合理化了这两个系列化合物的结合常数的差异。
• Method for preparing cyclic sulfamides and their use for the synthesis
  申请人：The Du Pont Merck Pharmaceutical Company

  公开号：US05506355A1

  公开（公告）日：1996-04-09

  The present invention discloses processes for the preparation of substituted cyclic sulfamides which are useful as intermediates for the synthesis of cyclic sulfamide human immunodeficiency virus (HIV) protease inhibitors. Such substituted cyclic sulfamide intermediates contain a cyclic acetal-protected diol.

  本发明公开了制备替代环磺酰胺的方法，这些方法可用作合成环磺酰胺人类免疫缺陷病毒（HIV）蛋白酶抑制剂的中间体。这些替代环磺酰胺中间体包含一个环缩醛保护的二醇。
• Substituted bicyclic phosphoramides and derivatives thereof
  申请人：The DuPont Merck Pharmaceutical Company

  公开号：US05543517A1

  公开（公告）日：1996-08-06

  This invention relates to substituted bicyclic phosphoramides and derivatives thereof, useful as retroviral protease inhibitors and as standards and reagents in determining the ability of a potential pharmaceutical to inhibit viral replication or HIV protease, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.

  该发明涉及替代的双环磷酰胺及其衍生物，可用作逆转录病毒蛋白酶抑制剂，以及作为标准和试剂用于确定潜在药物抑制病毒复制或HIV蛋白酶的能力，以及包含这些化合物的药物组合物，以及使用这些化合物治疗病毒感染的方法。