2-chloro-8-methyl-(4H)-1,3,2-benzodioxaphosphorin-2-oxide

• 分子结构分类: 有机化合物 - 苯类化合物
• 英文名称: 2-chloro-8-methyl-(4H)-1,3,2-benzodioxaphosphorin-2-oxide
• 英文别名: 2-chloro-8-methyl-4H-1,3,2-benzodioxaphosphorin-2-oxide；2-chloro-8-methyl-4H-benzo[d][1,3,2]dioxaphospholane；3-methyl-cyclosaligenylphosphorchloridate；2-chloro-8-methyl-4H-1,3,2lambda5-benzodioxaphosphinine 2-oxide；2-chloro-8-methyl-4H-1,3,2λ5-benzodioxaphosphinine 2-oxide
• 化学式: C₈H₈ClO₃P
• 分子量: 218.576
• InChiKey: REUCBJTWELKQKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-chloro-8-methyl-(4H)-1,3,2-benzodioxaphosphorin-2-oxide 在 N,N-双(苯基亚甲基)-1,2-乙二胺 、 copper(II) bis(trifluoromethanesulfonate) 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 7.5h， 生成 1-[(2R,4S,5S)-4-azido-5-[[(2S)-8-methyl-2-oxo-4H-1,3,2lambda5-benzodioxaphosphinin-2-yl]oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione
  参考文献：
  名称：

  Diastereoselective Synthesis of cycloSaligenyl-Nucleosyl-Phosphotriesters

  摘要：

  AbstractA diastereoselective synthesis of cycloSal‐phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal‐pronucleotides. In previously described synthesis routes, the cycloSal‐compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5‐methyl‐cycloSal‐phosphotriesters in 48 and ≥95 % de (de=diastereomeric excess). However, this approach failed to give the important group of 3‐substituted cycloSal‐nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (RP)‐ and (SP)‐3‐methyl‐cycloSal‐phosphotriesters as well. The antiviral activity was found to be five‐ to 20‐fold different between the two individual diastereomers, which proved the importance of this approach.

  DOI：

  10.1002/chem.201002657
• 作为产物：
  描述：

  3-甲基水杨酸 在 lithium aluminium tetrahydride 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 生成 2-chloro-8-methyl-(4H)-1,3,2-benzodioxaphosphorin-2-oxide
  参考文献：
  名称：

  Diastereoselective Synthesis of cycloSaligenyl-Nucleosyl-Phosphotriesters

  摘要：

  AbstractA diastereoselective synthesis of cycloSal‐phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal‐pronucleotides. In previously described synthesis routes, the cycloSal‐compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5‐methyl‐cycloSal‐phosphotriesters in 48 and ≥95 % de (de=diastereomeric excess). However, this approach failed to give the important group of 3‐substituted cycloSal‐nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (RP)‐ and (SP)‐3‐methyl‐cycloSal‐phosphotriesters as well. The antiviral activity was found to be five‐ to 20‐fold different between the two individual diastereomers, which proved the importance of this approach.

  DOI：

  10.1002/chem.201002657

文献信息

• [EN] SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF<br/>[FR] NUCLÉOSIDES, NUCLÉOTIDES SUBSTITUÉS ET LEURS ANALOGUES
  申请人：ALIOS BIOPHARMA INC

  公开号：WO2014209979A1

  公开（公告）日：2014-12-31

  Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a norovirus, with a nucleoside, a nucleotide and an analog thereof.

  本文揭示了核苷、核苷酸及其类似物，包括一个或多个核苷、核苷酸及其类似物的药物组合物，以及它们的合成方法。本文还揭示了利用核苷、核苷酸及其类似物改善和/或治疗疾病和/或病况的方法，包括使用核苷、核苷酸和其类似物治疗诺如病毒感染的方法。
• Divergent Synthesis and Biological Evaluation of Carbocyclic α-, <i>iso</i>- and 3′-<i>epi</i>-Nucleosides and their Lipophilic Nucleotide Prodrugs
  作者：Chris Meier、Olaf Ludek、Tobias Krämer、Jan Balzarini

  DOI：10.1055/s-2006-926411

  日期：2006.4

  A new divergent approach towards carbocyclic α-, iso- and 3′-epi-nucleosides starting from enantiomerically pure (1S,2R)-2-benzyloxymethylcyclopent-3-enol (5) is described. In the key step, isomeric cyclopentanols were condensed with a N3-protected pyrimidine nucleobase using a modified Mitsunobu protocol. Moreover, the conversion into the cycloSal-pronucleotides and the effect of the orientation of the nucleobase on anti-HIV activity are reported.

  报道了一种从手性纯的(1S,2R)-2-苄氧甲基环戊-3-烯醇(5)出发合成碳环α-、异-和3′-表-核苷的新分岔方法。在关键步骤中，异构环戊醇与N3保护的嘧啶核碱通过改进的Mitsunobu反应进行缩合。此外，还报道了其转化为环硫酸核苷前体的过程以及核碱取向对HIV抑制活性的影响。
• Synthesis and Antiviral Evaluation of Carbocyclic 3′-Azidothymidine (AZT) Analogues and TheircycloSal-Phosphate Triesters
  作者：Olaf R. Ludek、Jan Balzarini、Chris Meier

  DOI：10.1002/ejoc.200500719

  日期：2006.2

  Carbocyclic analogues of the anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) were synthesized. Starting from the enantiomerically pure carbocyclic 2′-deoxythymidine 2, four different carbocyclic AZT analogues 2,4–6 were prepared. Moreover, the nucleoside analogues were converted into their membrane-permeable cycloSal-phosphate triesters. All compounds were tested in vitro for their anti-HIV

  合成了抗 HIV 双脱氧核苷 3'-叠氮基-3'-脱氧胸苷 AZT (1) 的碳环类似物。从对映体纯碳环 2'-脱氧胸苷 2 开始，制备了四种不同的碳环 AZT 类似物 2,4-6。此外，核苷类似物被转化为它们的膜渗透性环磷酸三酯。所有化合物都在体外测试了它们在人 T 淋巴细胞中的抗 HIV 活性 (CEM/0)。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
• Stereoselective Synthesis and Antiviral Activity of Methyl-Substituted <i>cyclo</i>Sal-Pronucleotides
  作者：Edwuin H. Rios Morales、Jan Balzarini、Chris Meier

  DOI：10.1021/jm3008085

  日期：2012.8.23

  Methyl-substituted cycloSal-pronucleotides of d4TMP were synthesized with high diastereoselectivities in satisfying chemical yields. The individual diastereomers were tested against HIV-1 and HIV-2 infected wild-type CEM/0 and HIV-2 infected thymidine kinase deficient CEM cells. All diastereomers tested showed significant antiviral activity in CEM/0 and strong activity in CEM/TK– cell cultures. The

  合成的d4TMP的甲基取代的环Sal-前核苷酸具有很高的非对映选择性，可以满足化学收率。测试了各个非对映异构体针对HIV-1和HIV-2感染的野生型CEM / 0和HIV-2感染的胸苷激酶缺陷型CEM细胞的能力。所有测试的非对映异构体在CEM / 0中均表现出显着的抗病毒活性，在CEM / TK –细胞培养物中具有很强的活性。抗病毒活性强烈依赖于磷酸酯基团的手性和环Sal部分中甲基的位置。在CEM / TK中–细胞培养物中抗病毒效力的差异被发现为7至20倍。在水性磷酸盐缓冲液和CEM / 0细胞提取物中研究了每种非对映异构体的稳定性。发现半衰期有很大差异。基于通过反相HPLC获得的保留时间，进行了甲基取代的环Sal三酯的相对亲脂性的比较。获得的结果清楚地证实了环Sal-原核苷酸的非对映选择性合成的重要性。
• Diastereoselective Synthesis of cycloSaligenyl-Nucleosyl-Phosphotriesters
  作者：Edwuin H. Rios Morales、Jan Balzarini、Chris Meier

  DOI：10.1002/chem.201002657

  日期：2011.2.1

  AbstractA diastereoselective synthesis of cycloSal‐phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal‐pronucleotides. In previously described synthesis routes, the cycloSal‐compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5‐methyl‐cycloSal‐phosphotriesters in 48 and ≥95 % de (de=diastereomeric excess). However, this approach failed to give the important group of 3‐substituted cycloSal‐nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (RP)‐ and (SP)‐3‐methyl‐cycloSal‐phosphotriesters as well. The antiviral activity was found to be five‐ to 20‐fold different between the two individual diastereomers, which proved the importance of this approach.