(2,6-dichlorophenylacetyl)imidazolide | 221121-34-2

• 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: (2,6-dichlorophenylacetyl)imidazolide
• 英文别名: 2-(2,6-Dichlorophenyl)-1-(1H-imidazol-1-yl)ethanone；2-(2,6-dichlorophenyl)-1-imidazol-1-ylethanone
• CAS: 221121-34-2
• 化学式: C₁₁H₈Cl₂N₂O
• 分子量: 255.103
• InChiKey: FBWYTADBOGGPMZ-UHFFFAOYSA-N

物化性质

• 沸点：
  419.4±55.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  34.9
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2,6-dichlorophenylacetyl)imidazolide 在 sodium ethanolate 、 三乙胺 、 magnesium chloride 作用下， 反应 9.0h， 生成 6-(2,6-dichlorophenylmethyl)-3,4-dihydro-2-thiopyrimidin-4(3H)-one
  参考文献：
  名称：

  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

  摘要：

  Molecular modeling analysis of compounds belonging to the recently published series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.

  DOI：

  10.1021/jm980260f
• 作为产物：
  描述：

  2,6-二氯苯乙酸 、 N,N'-羰基二咪唑 以 乙腈 为溶剂， 生成 (2,6-dichlorophenylacetyl)imidazolide
  参考文献：
  名称：

  具有亚纳摩尔级抗HIV-1活性的新S-DABO衍生物的平行溶液相和微波辅助合成。

  摘要：

  已经建立了用于平行溶液相合成的简单而有效的方法，以获得一系列硫尿嘧啶，然后在微波辐射下选择性地将S-苄基化，得到新的S-DABO。生物筛选导致鉴定出对高度纯化的重组人免疫缺陷病毒1型（HIV-1）逆转录酶（RT）酶（野生型和突变型）和野生型（wt）和突变型HIV具有纳摩尔活性的化合物-1株。特别是，发现20种是迄今为止报道的最有效的S-DABO（针对分离的wt酶的ID50 = 26 nM），对wt和多抗性病毒（IRLL98）HIV-1菌株均具有亚纳摩尔活性（EC50 <0.14 nM和EC50分别为0.22 nM）。

  DOI：

  10.1021/jm050744t

文献信息

• Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor
  作者：Jeffery Richardson、Kevin P. Cole、Amy C. DeBaillie、Junliang Hao、Jared Piper、Peter Houghton、John Rizzo、Mo Jia、Peng Liu、Ping Huang、Katarina Kadlecikova、Conchita F. Garcia、Daniel S. Richards

  DOI：10.1021/acs.oprd.0c00229

  日期：2020.11.20

  (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, including unexpected issues that arose during cryogenic addition of MeLi to a key imine intermediate and the use of flow chemistry to enable large-scale production. Ultimately, a process that was used to deliver >100 kg of API to support

  概述了礼来D1阳性变构调节剂（PAM）甲维达烯（LY3154207）及其羟基苯甲酸酯共晶体从早期药物化学到大规模生产化学合成的过程。在几代合成过程中概述了解决这些问题所采取的问题和步骤，包括在将MeLi低温加至关键亚胺中间体中以及使用流化法实现大规模生产过程中出现的意外问题。最终，描述了一种用于输送> 100千克API以支持正在进行的临床试验的过程。
• Synthesis and biological evaluation of novel 2-(substituted phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs
  作者：Mingyan Yu、Xinyong Liu、Zhenyu Li、Shuai Liu、Christophe Pannecouque、Erik De Clercq

  DOI：10.1016/j.bmc.2009.09.035

  日期：2009.11

  A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC50 ranging from 4.48 μM to 0.18 μM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2

  设计并合成了一系列新颖的2-（苯基氨基羰基甲硫基）-6-（2,6-二氯苄基）-嘧啶-4（3 H）-。对所有这些新化合物在MT-4细胞中的抗HIV活性进行了评估。这些新化合物中的大多数显示出对野生型HIV-1的中度至强效活性，EC 50为4.48μM至0.18μM。其中，2-[（（4-溴苯基氨基）羰基甲硫基] -6-（2,6-二氯苄基）-5-甲基嘧啶-4（3 H）-一个4b3被确定为最有前途的化合物（EC 50 = 0.18±0.06 μM，CC 50 > 243.56μM，SI> 1326）。讨论了这些新同源物的构效关系（SAR）。
• Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase: Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants
  作者：Claudia Mugnaini、Maddalena Alongi、Andrea Togninelli、Harsukh Gevariya、Antonella Brizzi、Fabrizio Manetti、Cesare Bernardini、Lucilla Angeli、Andrea Tafi、Luca Bellucci、Federico Corelli、Silvio Massa、Giovanni Maga、Alberta Samuele、Marcella Facchini、Imma Clotet-Codina、Mercedes Armand-Ugón、José A. Esté、Maurizio Botta

  DOI：10.1021/jm0708230

  日期：2007.12.27

  A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.
• 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3<i>H</i>)-ones, a Series of Anti-HIV-1 Agents of the Dihydro-alkoxy-benzyl-oxopyrimidine Family with Peculiar Structure−Activity Relationship Profile
  作者：Maxim B. Nawrozkij、Dante Rotili、Domenico Tarantino、Giorgia Botta、Alexandre S. Eremiychuk、Ira Musmuca、Rino Ragno、Alberta Samuele、Samantha Zanoli、Mercedes Armand-Ugón、Imma Clotet-Codina、Ivan A. Novakov、Boris S. Orlinson、Giovanni Maga、José A. Esté、Marino Artico、Antonello Mai

  DOI：10.1021/jm800340w

  日期：2008.8.1

  A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl-S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L1001 mutated RTs) assays, compounds carrying an ethylliso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.
• Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethyl-substituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors
  作者：Yue-Ping Wang、Fen-Er Chen、Erik De Clercq、Jan Balzarini、Christophe Pannecouque

  DOI：10.1016/j.ejmech.2008.06.028

  日期：2009.3

  A series of new 5-alkyl-2-benzylsulfanylpyrimidin-4(3H)-ones (5a-y) bearing different substituted arylmethyl moieties at the C-6 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against HIV-1 and HIV-2 in MT-4 cell cultures. The majority of the title compounds showed moderate to good activities against HIV-1 with an IC50 range from 6.67 mu M to 0.12 mu M. Among them, 6-(3,5-dimethylbenzy]) analogue 5q exhibited the most potent anti-HIV-1 activity (IC50 = 0.12 mu M, SI > 2642), which was about 40-fold more active than the reference compounds 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 2',3'-dideoxyinosine (DDI). The structure-activity relationships (SARs) of these new congeners were further discussed. (C) 2008 Elsevier Masson SAS. All rights reserved.