(4R,5R,6R)-tetrahydro-1,3-bis[(3-carbomethoxyphenyl)methyl]-5-hydroxy-4-(2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone | 167824-16-0

• 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: (4R,5R,6R)-tetrahydro-1,3-bis[(3-carbomethoxyphenyl)methyl]-5-hydroxy-4-(2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone
• 英文别名: methyl 3-[[(4R,5R,6R)-4-benzyl-5-hydroxy-3-[(3-methoxycarbonylphenyl)methyl]-2-oxo-6-(2-phenylethyl)-1,3-diazinan-1-yl]methyl]benzoate
• CAS: 167824-16-0
• 化学式: C₃₇H₃₈N₂O₆
• 分子量: 606.719
• InChiKey: HJFACERSEJRFRX-CKOYEXALSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  96.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4R,5R,6R)-tetrahydro-1,3-bis[(3-carbomethoxyphenyl)methyl]-5-hydroxy-4-(2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone 在 sodium hydroxide 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 21.0h， 生成 (4S,5R)-dimethyl-3,3'-{[4-(1(S)-hydroxy-2-phenylethyl)-2-oxo-5-(2-phenylethyl)-1,3-imidazolidinyl]bis(methylene)}bis(benzoate)
  参考文献：
  名称：

  Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors

  摘要：

  We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.

  DOI：

  10.1021/jo980533e
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 生成 (4R,5R,6R)-tetrahydro-1,3-bis[(3-carbomethoxyphenyl)methyl]-5-hydroxy-4-(2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone
  参考文献：
  名称：

  四氢嘧啶酮的设计，合成和评估，作为非肽类HIV蛋白酶抑制剂一般方法的一个例子。

  摘要：

  对HIV蛋白酶（HIVPR）抑制剂的环状脲类设计的重新审查提出了设计新型非肽环状HIVPR抑制剂的一般方法。该过程涉及线性HIVPR抑制剂的核心过渡态等位体的立体化学中心的反转，以及使用合适的环化试剂环化所得核心。例如，该方法应用于HIVPR抑制剂的二氨基醇类，得到四氢嘧啶酮。四氢嘧啶酮的构象分析及其与HIVPR活性位点相互作用的模型表明，修饰导致了非常有效的HIVPR抑制剂（24种，Ki = 0.018 nM）。具有HIVPR的24配合物的X射线晶体学结构证实了分析和模型预测。

  DOI：

  10.1021/jm970081i

文献信息

• Design, Synthesis, and Evaluation of Tetrahydropyrimidinones as an Example of a General Approach to Nonpeptide HIV Protease Inhibitors
  作者：George V. De Lucca、Jing Liang、Paul E. Aldrich、Joe Calabrese、Beverly Cordova、Ronald M. Klabe、Marlene M. Rayner、Chong-Hwan Chang

  DOI：10.1021/jm970081i

  日期：1997.5.1

  Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this

  对HIV蛋白酶（HIVPR）抑制剂的环状脲类设计的重新审查提出了设计新型非肽环状HIVPR抑制剂的一般方法。该过程涉及线性HIVPR抑制剂的核心过渡态等位体的立体化学中心的反转，以及使用合适的环化试剂环化所得核心。例如，该方法应用于HIVPR抑制剂的二氨基醇类，得到四氢嘧啶酮。四氢嘧啶酮的构象分析及其与HIVPR活性位点相互作用的模型表明，修饰导致了非常有效的HIVPR抑制剂（24种，Ki = 0.018 nM）。具有HIVPR的24配合物的X射线晶体学结构证实了分析和模型预测。
• Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors
  作者：George V. De Lucca

  DOI：10.1021/jo980533e

  日期：1998.7.1

  We have discovered that hexahydro-5,6-dihydroxy-1,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (S(N)2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with:the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N'-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.