3-isoxazolecarboxylic acid 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester | 216962-12-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-isoxazolecarboxylic acid 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester
• 英文别名: 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-3-isoxazolecarboxylic acid ethyl ester；ethyl 4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-5-methyl-1,2-oxazole-3-carboxylate；ethyl 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)isoxazole-3-carboxylate；Ethyl 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-1,2-oxazole-3-carboxylate
• CAS: 216962-12-8
• 化学式: C₁₄H₂₁NO₅
• 分子量: 283.324
• InChiKey: DSJBHKDMJMLYPR-UHFFFAOYSA-N

物化性质

• 沸点：
  396.0±42.0 °C(Predicted)
• 密度：
  1.105±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  70.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-isoxazolecarboxylic acid 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester 在 N-溴代丁二酰亚胺(NBS) 、 caesium carbonate 、 对甲苯磺酸 、 sodium hydroxide 作用下， 以 四氯化碳 、 丙酮 为溶剂， 生成 4-(1-(2-(3,5-bis(trifluoromethyl)phenyl)hydrazono)ethyl)-5-(4-(trifluoromethyl)benzyl)isoxazole-3-carboxylic acid
  参考文献：
  名称：

  Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system xc- cystine/glutamate exchanger

  摘要：

  The system x(c)(-) antiporter is a plasma membrane transporter that mediates the exchange of extracellular L-cystine with intracellular L-glutamate. This exchange is significant within the context of the CNS because the import of L-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of L-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system x(c)(-) blockers, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at system x(c)(-). In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block system x(c)(-)-mediated uptake of H-3-L-glutamate into SNB-19 cells by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These dialyl-isoxazoles should be of value in assessing the physiological roles and molecular pharmacology of system x(c)(-). (C) 2013 Published by Elsevier Ltd.

  DOI：

  10.1016/j.neuint.2013.11.012
• 作为产物：
  描述：

  2,2-二甲基-1,3-丙二醇 、 4-乙酰基-5-甲基异恶唑-3-甲酸乙酯 在 对甲苯磺酸 作用下， 以 苯 为溶剂， 反应 18.0h， 以2.337 g的产率得到3-isoxazolecarboxylic acid 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester
  参考文献：
  名称：

  微波条件下苄基溴化物的 Suzuki-Miyaura 交叉偶联

  摘要：

  已经开发了一种在微波条件下用于苄基 Suzuki-Miyaura 交叉偶联的程序。这些条件允许杂环化合物偶联。发现的最佳条件是 Pd(OAc) 2，JohnPhos 作为催化剂和配体，碳酸钾作为碱，DMF 作为溶剂。使用这些条件，合成了结构多样的化合物库。

  DOI：

  10.1016/j.tetlet.2011.08.096

文献信息

• The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors
  作者：Christina A. Gates、Donald S. Backos、Philip Reigan、Nicholas R. Natale

  DOI：10.3390/molecules28196800

  日期：——

  Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of

  异恶唑并[3,4-d]哒嗪酮 ([3,4-d]s) 先前已被证明对代谢型谷氨酸受体 (mGluR) 亚型 2 和 4 具有选择性正向调节作用，而与 mGluR1a、mGluR5 没有功能性交叉反应，或 mGluR8。正如同源模型所表明的，制备了额外的类似物以进入更多的变构口袋并实现更高的结合亲和力。生成了两组不同的类似物。一种使用完全形成的[3,4-d]和带有或不带有卤素的N6-芳基。它们在异恶唑的 C3 处成功进行了选择性横向金属化和亲电猝灭 (LM&EQ)。在第二组类似物中，通过 4-苯乙酰基-3-乙氧羰基-5-甲基异恶唑与相应的肼缩合，在 [3,4-d] 环的 C4 位引入苯基，生成 3 ,4-ds 2b 和 2j 至 2n。
• Catalytic Asymmetric Synthesis of Glutamate Analogues
  作者：David J. Burkhart、Andrew R. McKenzie、Jared K. Nelson、Katherine I. Myers、Xue Zhao、Kathy R. Magnusson、Nicholas R. Natale

  DOI：10.1021/ol049619m

  日期：2004.4.1

  Utilizing our lateral metalation coupled with Jacobsen's catalytic asymmetric amino nitrile synthesis, we have demonstrated the ability to synthesize isoxazole-containing amino acid glutamate analogues in high yield and high enantiomeric excesses. Chiral centers alpha or beta at the C-5 position do not detract from diastereoselectivity of the Jacobsen-Strecker reaction.
• Isoxazole analogues bind the System xc- transporter: Structure–activity relationship and pharmacophore model
  作者：Sarjubhai A. Patel、Trideep Rajale、Erin O’Brien、David J. Burkhart、Jared K. Nelson、Brendan Twamley、Alex Blumenfeld、Monika I. Szabon-Watola、John M. Gerdes、Richard J. Bridges、Nicholas R. Natale

  DOI：10.1016/j.bmc.2009.11.001

  日期：2010.1

  Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System x(c)(-). Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System x(c)(-), the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y' = 3,5-(CF3)(2), which both inhibited glutamate uptake by the System x(c)(-) transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. (C) 2009 Elsevier Ltd. All rights reserved.
• An improved procedure for the lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate
  作者：David J Burkhart、Peiwen Zhou、Alex Blumenfeld、Brendan Twamley、Nicholas R Natale

  DOI：10.1016/s0040-4020(01)00781-5

  日期：2001.9

  Ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate was smoothly lithiated at the 5-methyl position, when the 4-acetyl group was protected with a 5,5-dimethyl-1,3-dioxanyl group. The lithio anion was quenched with a variety of electrophiles such as alkyl halides, aldehydes, TMSCl, and Me3SnCl in good to excellent yields. The lithiation of the unprotected compound and the 4-acetyl group protected as 1,3-dioxolanyl both failed. The effects of different bases have been investigated and the addition of LiCl significantly increased yields. Based on variable temperature NMR studies the 5,5-dimethyl-1,3-dioxanyl group appears to occupy a single chair conformation which may facilitate lateral metalation. This represents a facile entry into 5-functionalized 3-isoxazolyl carboxylic acid derivatives as prodrugs for the AMPA glutamate neurotransmitters of the central nervous system. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate with 5,5-dimethyl-1,3-dioxanyl as a directing group
  作者：Peiwen Zhou、N.R. Natale

  DOI：10.1016/s0040-4039(98)01782-1

  日期：1998.11

  Lateral lithiation of ethyl 4-acetyl-5-methyl-3-isoxazolyl carboxylate, a functionalized isoxazole AMPA analog, occurs cleanly at the C-5 methyl group with 5,5-dimethyl-1,3-dioxanyl as a directing group. The 4-acetyl isoxazole derivatives were transformed selectively by a modified Willgerodt-Kindler reaction into the corresponding homologated methyl esters after deprotection. (C) 1998 Elsevier Science Ltd. All rights reserved.