6-Benzyl-1-ethoxymethyl-5-1H-pyrimidine-2,4-dione | 347861-33-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-Benzyl-1-ethoxymethyl-5-1H-pyrimidine-2,4-dione
• 英文别名: 6-benzyl-1-ethoxymethyl-5-iodouracil；6-Benzyl-1-(ethoxymethyl)-5-iodo-pyrimidine-2,4-dione；6-benzyl-1-(ethoxymethyl)-5-iodopyrimidine-2,4-dione
• CAS: 347861-33-0
• 化学式: C₁₄H₁₅IN₂O₃
• 分子量: 386.189
• InChiKey: QNFFQALEPULKCG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-Benzyl-1-ethoxymethyl-5-1H-pyrimidine-2,4-dione 在 吡啶 、 四(三苯基膦)钯 、 N,N-二异丙基乙胺 作用下， 以 六甲基磷酰三胺 为溶剂， 反应 50.5h， 生成 6-Benzyl-1-ethoxymethyl-3-(4-methylbenzoyl)-5-vinyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Three Routes for the Synthesis of 6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde

  摘要：

  6-苄基-1-乙氧基甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲醛（1）是 MKC-442 的类似物，MKC-442 是一种非常有效的 HIV-1 逆转录酶抑制剂。化合物 1 通过三种不同的途径合成。6-苄基-1-乙氧基甲基-5-乙烯基-1H-嘧啶-2,4-二酮（7）是由 6-苄基-1H-嘧啶-2,4-二酮（2）通过碘化、N-1 烷基化、N-3 保护、钯（0）催化与四乙烯基锡偶联以及 N-3 去保护五个步骤合成的。最后，化合物 1 由 6-苄基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲腈（10）通过雷尼镍还原和 N-1 烷基化合成。有人尝试用化合物 7 作为 6-苄基-1-乙氧基甲基-5-环氧乙烷基-1H-嘧啶-2,4-二酮（11）的前体，将 7 与 MCPBA 反应，但化合物 11 反应性太强，被溶液中的间氯苯甲酸酯开环。两个中间体经过 N-1 烷基化，得到了在 C-5 位含有羟甲基（13）或氰基（14）的新 MKC-442 类似物。这些化合物均未显示出对变异 HIV-1 病毒（Tyr181Cys）的活性，但在 C-5 位分别含有碘基或乙烯基的中间体 4 和 7 对野生型 HIV-1 具有良好的活性。

  DOI：

  10.1055/s-2001-12352
• 作为产物：
  描述：

  6-苄基-2-硫脲嘧啶 在 N,O-双三甲硅基乙酰胺 、 碘 、 lead dioxide 、 溶剂黄146 、 氯乙酸 作用下， 以 氯仿 、 水 为溶剂， 反应 40.5h， 生成 6-Benzyl-1-ethoxymethyl-5-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of 1-[(2-Benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with an Improved Drug Resistance Profile

  摘要：

  Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.

  DOI：

  10.1021/jm201506e

文献信息

• Design, Synthesis, and Biological Evaluation of 1-[(2-Benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with an Improved Drug Resistance Profile
  作者：Xiaowei Wang、Jianfang Zhang、Yang Huang、Ruiping Wang、Liang Zhang、Kang Qiao、Li Li、Chang Liu、Yabo Ouyang、Weisi Xu、Zhili Zhang、Liangren Zhang、Yiming Shao、Shibo Jiang、Liying Ma、Junyi Liu

  DOI：10.1021/jm201506e

  日期：2012.3.8

  Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.
• Three Routes for the Synthesis of 6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde
  作者：Lene Petersen、Erik B. Pedersen、Claus Nielsen

  DOI：10.1055/s-2001-12352

  日期：——

  6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (1) is an analog of MKC-442, a very potent inhibitor of HIV-1 reverse transcriptase. Compound 1 was synthesized by three different routes. 6-Benzyl-1-ethoxymethyl-5-vinyl-1H-pyrimidine-2,4-dione (7) was synthesized in five steps from 6-benzyl-1H-pyrimidine-2,4-dione (2) by iodination; N-1 alkylation, N-3 protection, Pd(0) catalyzed coupling with tetravinyltin and then N-3 deprotection. Compound 7 was then cleaved with ozone to give compound 1. In another route compound 2 was hydroxymethylated, oxidized and N-1 alkylated to give compound 1. Finally, compound 1 was synthesized from 6-benzyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (10) by reduction with Raney Nickel followed by N-1 alkylation. An attempt was made to use compound 7 as a precursor for 6-benzyl-1-ethoxymethyl-5-oxiranyl-1H-pyrimidine-2,4-dione (11) by reacting 7 with MCPBA, but compound 11 was too reactive and was ring-opened by the m-chlorobenzoate present in the solution. Two intermediates were N-1 alkylated to give new MKC-442 analogs containing a hydroxymethyl group (13) or a cyano group (14) in the C-5 position. None of the compounds showed activity against the mutated HIV-1 virus (Tyr181Cys) but good activities were observed against wild-type HIV-1 for the intermediates 4 and 7 containing iodine or a vinyl group in the C-5 position, respectively.

  6-苄基-1-乙氧基甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲醛（1）是 MKC-442 的类似物，MKC-442 是一种非常有效的 HIV-1 逆转录酶抑制剂。化合物 1 通过三种不同的途径合成。6-苄基-1-乙氧基甲基-5-乙烯基-1H-嘧啶-2,4-二酮（7）是由 6-苄基-1H-嘧啶-2,4-二酮（2）通过碘化、N-1 烷基化、N-3 保护、钯（0）催化与四乙烯基锡偶联以及 N-3 去保护五个步骤合成的。最后，化合物 1 由 6-苄基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲腈（10）通过雷尼镍还原和 N-1 烷基化合成。有人尝试用化合物 7 作为 6-苄基-1-乙氧基甲基-5-环氧乙烷基-1H-嘧啶-2,4-二酮（11）的前体，将 7 与 MCPBA 反应，但化合物 11 反应性太强，被溶液中的间氯苯甲酸酯开环。两个中间体经过 N-1 烷基化，得到了在 C-5 位含有羟甲基（13）或氰基（14）的新 MKC-442 类似物。这些化合物均未显示出对变异 HIV-1 病毒（Tyr181Cys）的活性，但在 C-5 位分别含有碘基或乙烯基的中间体 4 和 7 对野生型 HIV-1 具有良好的活性。