N-(5-azido-6-chloropyridin-3-ylmethyl)morpholine | 321845-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-(5-azido-6-chloropyridin-3-ylmethyl)morpholine
• 英文别名: 4-[(5-Azido-6-chloropyridin-3-yl)methyl]morpholine
• CAS: 321845-15-2
• 化学式: C₁₀H₁₂ClN₅O
• 分子量: 253.691
• InChiKey: CRSHHTWHVFQLDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  39.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(5-azido-6-chloropyridin-3-ylmethyl)morpholine 在 氯甲酸乙酯 作用下， 反应 6.0h， 生成 5-azido-6-chloropyridin-3-ylmethyl chloride
  参考文献：
  名称：

  叠氮吡啶基新烟碱样探针的结构特征赋予了对哺乳动物alpha4beta2和果蝇烟碱样受体的高亲和力和选择性。

  摘要：

  新烟碱类杀虫剂（如N-（6-氯吡啶-3--3-甲基）-2-硝基亚氨基咪唑烷（吡虫啉））对昆虫的毒性要比哺乳动物高，这在很大程度上是由于在相应的烟碱型乙酰胆碱受体（nAChRs）具有靶位点特异性。我们建议具有质子化的N-未取代的亚胺或同等取代基的新烟碱能识别哺乳动物alpha4beta2 nAChR的阴离子亚位，而新烟碱杀虫剂的带负电（delta（-））尖端则与昆虫nAChR的假定阳离子亚位相互作用。可以通过使用两个仅在N-未取代的亚胺与带负电的（delta（-））尖端不同的光亲和探针来检验此假设。为结合三个部分的化合物开发了合成方法：吡啶-3-基甲基或6-氯吡啶-3-基甲基及其4-和5-叠氮基类似物；咪唑烷，4-咪唑啉或4-噻唑啉; N-未取代的亚胺，硝基亚胺，氰胺或硝基亚甲基。结构活性研究比较了哺乳动物alpha4beta2 nAChR中的[（3）H]烟碱结合和果蝇nAChR中的[（3）

  DOI：

  10.1021/jm010508s
• 作为产物：
  描述：

  2-氯-5-氯甲基吡啶 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 生成 N-(5-azido-6-chloropyridin-3-ylmethyl)morpholine
  参考文献：
  名称：

  Azido-Neonicotinoids as Candidate Photoaffinity Probes for Insect Nicotinic Acetylcholine Receptors [1]

  摘要：

  新烟碱类杀虫剂是最成功的化学类杀虫剂之一，2001年销售额超过6.3亿美元，主要归功于良好的市场表现，如吡虫啉和噻虫嗪。这些化合物的靶点是昆虫的尼古丁乙酰胆碱受体（nAChRs），对多种吸食和咀嚼昆虫具有高效作用。与其他新烟碱类杀虫剂销售产品相比，噻虫嗪以不同的方式结合，可能是与蚜虫的nAChRs上的不同位点结合。为了进一步了解不同的结合模式，开始了一个应用光致亲和标记技术的研究项目。从6-氯吡啶-3-甲基氯化物中经过三步制备了一系列新型候选光致亲和探针，其中包含5-叠氮-6-氯吡啶-3-基甲基基团。这些探针对桃蚜具有良好至优异的接触/摄食和系统活性，但对黑豆蚜、褐飞虱、棉铃虫和斜纹夜蛾至少比新烟碱类杀虫剂销售产品低4至16倍。总的来说，在6-氯吡啶-3-甲基取代基的C（5）位置引入叠氮基团导致了活性降低以及害虫谱变窄。在与[3H]吡虫啉竞争结合实验中，含有5-叠氮-6-氯吡啶-3-基甲基基团的吡虫啉、克虫啉、噻虫啉和噻虫嗪类似物在蚜虫和桃蚜的nAChRs上显示出高位移能力（Ki值：2至27 nM），表明这些化合物是有价值的候选光致亲和探针。考虑到生物筛选活性和受体结合效力，1-（5-叠氮-6-氯吡啶-3-基甲基）-2-硝基亚咪唑啉、N-（5-叠氮-6-氯吡啶-3-基甲基）-N？-甲基-N？-硝基胍和3-（5-叠氮-6-氯吡啶-3-基甲基）-2-氰基亚噻唑啉被确定为首选的候选新烟碱类光致亲和探针，用于研究吡虫啉结合位点。

  DOI：

  10.2533/000942903777678605

文献信息

• Structural Features of Azidopyridinyl Neonicotinoid Probes Conferring High Affinity and Selectivity for Mammalian α4β2 and <i>Drosophila</i> Nicotinic Receptors
  作者：Nanjing Zhang、Motohiro Tomizawa、John E. Casida

  DOI：10.1021/jm010508s

  日期：2002.6.1

  toxicity of neonicotinoid insecticides such as N-(6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (imidacloprid) to insects than mammals is due in large part to target site specificity at the corresponding nicotinic acetylcholine receptors (nAChRs). We propose that neonicotinoids with a protonated N-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian alpha4beta2

  新烟碱类杀虫剂（如N-（6-氯吡啶-3--3-甲基）-2-硝基亚氨基咪唑烷（吡虫啉））对昆虫的毒性要比哺乳动物高，这在很大程度上是由于在相应的烟碱型乙酰胆碱受体（nAChRs）具有靶位点特异性。我们建议具有质子化的N-未取代的亚胺或同等取代基的新烟碱能识别哺乳动物alpha4beta2 nAChR的阴离子亚位，而新烟碱杀虫剂的带负电（delta（-））尖端则与昆虫nAChR的假定阳离子亚位相互作用。可以通过使用两个仅在N-未取代的亚胺与带负电的（delta（-））尖端不同的光亲和探针来检验此假设。为结合三个部分的化合物开发了合成方法：吡啶-3-基甲基或6-氯吡啶-3-基甲基及其4-和5-叠氮基类似物；咪唑烷，4-咪唑啉或4-噻唑啉; N-未取代的亚胺，硝基亚胺，氰胺或硝基亚甲基。结构活性研究比较了哺乳动物alpha4beta2 nAChR中的[（3）H]烟碱结合和果蝇nAChR中的[（3）
• 5-Azidoimidacloprid and an Acyclic Analogue as Candidate Photoaffinity Probes for Mammalian and Insect Nicotinic Acetylcholine Receptors
  作者：Shinzo Kagabu、Peter Maienfisch、Aiguo Zhang、Joaquin Granda-Minones、Joerg Haettenschwiler、Hartmut Kayser、Thomas Maetzke、John E. Casida

  DOI：10.1021/jm000240p

  日期：2000.12.1

  The 5-azido analogue:of:the major, insecticide imidacloprid, 1-(5-azido-6-chloropyridin-3-ylmethy)-2-nitroiminoimidazolidine (1), and an acyclic analogue, N-(5-azido-6-chloropyridin-3-ylmethyl)-N'-methyl-N " -nitroguanidine (2), were prepared in good yields as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors (nAChRs). The essential intermediate was 5-azido-6-chloropyridin-3-ylmethyl chloride (3) prepared in two: ways: from, 6-chloro-5-nitronicotinic acid by selective reduction and then diazotization, and from N-(6-chloropyridin-3-ylmethyl)morpholine by an electrophilic azide introduction with lithium diisopropylamide: followed by,chlorine substitution of morpholine with Ethyl chloroformate: Coupling of 3 with 2-nitroiminoimidazolidine gave 1, Conversion of 3 to 2 was achieved in good,yields via the hexahydrotriazine intermediate 14. Fortuitously, the azido substituent in land 2 increases' the affinity 7-79-fold for rat brain and recombinant (alpha4 beta2 nAChRs:(K(i)s 4.4-60 nM competing with [H-3](-)-nicotine) while maintaining high potency on both insect nAChRs (Drosophila and Myzus) (K(i)s 1-5 nM competing with [H-3]imidacloprid). Azidopyridinyl compounds 1 and 2 are therefore candidate photoaffinity probes for characterization. of both mammalian and insect receptors.
• Azido-Neonicotinoids as Candidate Photoaffinity Probes for Insect Nicotinic Acetylcholine Receptors [1]
  作者：Peter Maienfisch、Joerg Haettenschwiler、Alfred Rindlisbacher、Arnaud Decock、Henning Wellmann、Hartmut Kayser

  DOI：10.2533/000942903777678605

  日期：——

  The neonicotinoids are the most successful chemical class of insecticides reaching sales of more than 630 Mio $ in 2001, mainly due to the excellent market performance of imidacloprid and thiamethoxam. The insect nicotinic acetylcholine receptors (nAChRs) are the targets for these compounds, which are highly effective against a variety of sucking and chewing insects. Compared with the other neonicotinoid sales products, thiamethoxam binds in a different way, possibly to a different site of nAChRs in aphids. To gain further insight into the different modes of binding, a research program applying the photoaffinity labeling technique was started. A series of novel candidate photoaffinity probes containing a 5-azido-6-chloropyridin-3-ylmethyl group were prepared from 5-azido-6-chloropyridin-3-ylmethyl chloride, which was obtained in three steps from 6-chloropyridin-3-ylmethyl chloride. These probes showed good to excellent contact/feeding and systemic activity against Myzus persicae, however, they were at least 4- to 16-fold less effective against Aphis craccivora, Nilaparvata lugens, Spodoptera littoralis, and Diabrotica balteata than the neonicotinoid sales products. In general, the introduction of an azide group at C(5) of the 6-chloropyridin-3-ylmethyl substituent resulted in reduced potency as well as in a narrower pest spectrum. In competition binding assays with [3H]imidacloprid, analogues of imidacloprid, clothianidin, thiacloprid and thiamethoxam containing a 5-azido-6-chloropyridin-3-ylmethyl group showed high displacing potency with nAChRs from Aphis and Myzus (Ki values: 2 to 27 nM) suggesting that these compounds are valuable candidate photoaffinity probes. Taking into account the biological screening activity as well as the receptor binding potency, 1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroimino-imidazolidine, N-(5-azido-6-chloropyridin-3-ylmethyl)-N?-methyl-N?-nitroguanidine and 3-(5-azido-6-chloropyridin-3-ylmethyl)-2-cyanoimino-thiazolidine were identified as the preferred candidate neonicotinoid photoaffinity probes to study the imidacloprid binding site.

  新烟碱类杀虫剂是最成功的化学类杀虫剂之一，2001年销售额超过6.3亿美元，主要归功于良好的市场表现，如吡虫啉和噻虫嗪。这些化合物的靶点是昆虫的尼古丁乙酰胆碱受体（nAChRs），对多种吸食和咀嚼昆虫具有高效作用。与其他新烟碱类杀虫剂销售产品相比，噻虫嗪以不同的方式结合，可能是与蚜虫的nAChRs上的不同位点结合。为了进一步了解不同的结合模式，开始了一个应用光致亲和标记技术的研究项目。从6-氯吡啶-3-甲基氯化物中经过三步制备了一系列新型候选光致亲和探针，其中包含5-叠氮-6-氯吡啶-3-基甲基基团。这些探针对桃蚜具有良好至优异的接触/摄食和系统活性，但对黑豆蚜、褐飞虱、棉铃虫和斜纹夜蛾至少比新烟碱类杀虫剂销售产品低4至16倍。总的来说，在6-氯吡啶-3-甲基取代基的C（5）位置引入叠氮基团导致了活性降低以及害虫谱变窄。在与[3H]吡虫啉竞争结合实验中，含有5-叠氮-6-氯吡啶-3-基甲基基团的吡虫啉、克虫啉、噻虫啉和噻虫嗪类似物在蚜虫和桃蚜的nAChRs上显示出高位移能力（Ki值：2至27 nM），表明这些化合物是有价值的候选光致亲和探针。考虑到生物筛选活性和受体结合效力，1-（5-叠氮-6-氯吡啶-3-基甲基）-2-硝基亚咪唑啉、N-（5-叠氮-6-氯吡啶-3-基甲基）-N？-甲基-N？-硝基胍和3-（5-叠氮-6-氯吡啶-3-基甲基）-2-氰基亚噻唑啉被确定为首选的候选新烟碱类光致亲和探针，用于研究吡虫啉结合位点。