Acetic acid (4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-[1,3]diazepan-5-yl ester | 179894-02-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: Acetic acid (4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-[1,3]diazepan-5-yl ester
• 英文别名: [(4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-1,3-diazepan-5-yl] acetate
• CAS: 179894-02-1
• 化学式: C₂₁H₂₄N₂O₄
• 分子量: 368.433
• InChiKey: MSLOUSLQYGANBD-ZRNYENFQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  87.7
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Acetic acid (4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-[1,3]diazepan-5-yl ester 在 palladium on activated charcoal 氢氧化钾 、 氢溴酸 、 氢气 、 对甲苯磺酸 、 4,4'-二氨基二苯乙烯-2,2'-二磺酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 25.0 ℃ 、344.74 kPa 条件下， 反应 3.83h， 生成 (4R,5R,6R)-tetrahydro-5-(tetrahydropyran-2-yl-oxy)-4-(2-phenylethyl)-6-(phenylmethyl)-2(1H)-pyrimidinone
  参考文献：
  名称：

  Stereospecific Synthesis, Structure−Activity Relationship, and Oral Bioavailability of Tetrahydropyrimidin-2-one HIV Protease Inhibitors

  摘要：

  The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.

  DOI：

  10.1021/jm9803626
• 作为产物：
  描述：

  Cbz-D-苯丙氨醇 在 palladium on activated charcoal 盐酸 、 草酰氯 、 [VCl3(thf)3] 、 水 、 氢气 、 对甲苯磺酸 、 二甲基亚砜 、 三乙胺 、 N,N-二异丙基乙胺 、 锌 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 52.0h， 生成 Acetic acid (4R,5S,6S,7R)-4,7-dibenzyl-6-hydroxy-2-oxo-[1,3]diazepan-5-yl ester
  参考文献：
  名称：

  环状HIV蛋白酶抑制剂：合成，构象分析，P2 / P2'的结构活性关系和环状脲的分子识别。

  摘要：

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其

  DOI：

  10.1021/jm9602571

文献信息

• 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.