4,4-dimethyl-2-(4-phenyl-4H-pyridin-3-ylidene)-1,3-oxazolidine | 68981-78-2

• 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: 4,4-dimethyl-2-(4-phenyl-4H-pyridin-3-ylidene)-1,3-oxazolidine
• 英文别名: 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1,4-dihydro-4-phenylpyridine；3-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-4-phenyl-1,4-dihydro-pyridine
• CAS: 68981-78-2
• 化学式: C₁₆H₁₈N₂O
• 分子量: 254.332
• InChiKey: UYARQFCBHHEBLS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.98
• 重原子数：
  19.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  33.62
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  4,4-dimethyl-2-(4-phenyl-4H-pyridin-3-ylidene)-1,3-oxazolidine 在 盐酸 、 氯化亚砜 、 sulfur 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 35.5h， 生成 4-phenylpyridine-3-carboxylic acid methyl ester
  参考文献：
  名称：

  Identification and Characterization of m1 Selective Muscarinic Receptor Antagonists

  摘要：

  A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential mi selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [H-3]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R-1 = (CH2)(5)CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical mi antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.

  DOI：

  10.1021/jm980067l
• 作为产物：
  描述：

  烟酸 在 氯化亚砜 作用下， 生成 4,4-dimethyl-2-(4-phenyl-4H-pyridin-3-ylidene)-1,3-oxazolidine
  参考文献：
  名称：

  Meyers,A.I.; Gabel,R.A., Heterocycles, 1978, vol. 11, p. 133 - 138

  摘要：

  DOI：

文献信息

• Synthesis of 4,4-bis(2-methylphenyl)-3-butenyl (and butyl) analogs of 4-phenyl-1,4- and 6-phenyl-1,6-dihydropyridine-3-carboxylic acids and their evaluation as neuronal GABA-uptake inhibitors
  作者：Nadeem Iqbal、Zhong-Yong Wei、Glen B. Baker、Edward E. Knaus

  DOI：10.1139/v97-071

  日期：1997.6.1

  Treatment of 3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (13) with NaH–DMSO, and then reaction with 1,1-bis(2-methylphenyl)-4-bromobutane (12c) afforded 1-[4,4-bis(2-methylphenyl)butyl]-3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (14). Reaction of methyl nicotinate with 2.1 equivalents 12c or 1,1-bis(2-methylphenyl)-4-bromo-1-butene (11b) afforded 4,4-bis(2-methylphenyl)butyl 1-[4,4-bis(2-methylphenyl)butyl]pyridinium-3-carboxylate bromide (17) or 4,4-bis(2-methylphenyl)-3-butenyl 1-[4,4-bis(2-methylphenyl)-3-butenyl]pyridinium-3-carboxylate bromide (18), respectively. The nonregioselective reaction of the pyridinium salts (17/18) with PhMgCl in THF at −23 °C using a catalytic amount of CuI afforded a mixture of isomeric 4-phenyl-1,4-dihydropyridyl (21 or 22) and 6-phenyl-1,6-dihydropyridyl (27 or 28) products in a ratio of approximately 1:1. All attempts to hydrolyze the 4,4-bis(2-methylphenyl)butyl or 3-butenyl ester moiety of 21/22 or 27/28 to a carboxyl group resulted in decomposition products. In contrast, the corresponding 3-(2-cyanoethyl) esters (23, 24, 29, 30) were readily converted to the corresponding carboxyl analogs (25, 26, 31, 32) via a β-elimination reaction of acrylonitrile using the non-nucleophilic base DBU. The 4-phenyl-1,4-dihydropyridyl (14, 25, 26) and 6-phenyl-1,6-dihydropyridyl (27/28 or 31/32) compounds inhibited the in vitro uptake of [³H]GABA into striatal prisms in the 21–44% range at a 10⁻⁴ M test compound concentration, relative to the reference drug nipecotic acid (87% inhibition). Structure–activity correlations showed the dihydropyridyl C-3 substituent was a determinant of [³H]GABA uptake where the potency order was CO₂H > 2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl) > CO₂(CH₂)₃CH-(o-tolyl)₂ and CO₂(CH₂)₂CH=C-(o-tolyl)₂. Compounds possessing C-3 and (or) N-1 CO₂(CH₂)₃CH-(o-tolyl)₂ substituents were generally more potent than analogs having CO₂(CH₂)₂CH=C-(o-tolyl)₂ substituents. In general, 1,6-dihydropyridyl compounds were more potent than the corresponding 1,4-dihydropyridyl isomers. Keywords: 1,4- and 1,6-dihydropyridines, GABA-uptake inhibitors.

  将3-[2-(4,4-二甲基-4,5-二氢噁唑啉-2-基)]-4-苯基-1,4-二氢吡啶（13）与NaH-DMSO处理，然后与1,1-双(2-甲基苯基)-4-溴丁烷（12c）反应得到1-[4,4-双(2-甲基苯基)丁基]-3-[2-(4,4-二甲基-4,5-二氢噁唑啉-2-基)]-4-苯基-1,4-二氢吡啶（14）。 甲基烟酸酯与2.1当量的12c或1,1-双(2-甲基苯基)-4-溴-1-丁烯（11b）反应，得到4,4-双(2-甲基苯基)丁基1-[4,4-双(2-甲基苯基)丁基]吡啶-3-羧酸酯溴化物（17）或4,4-双(2-甲基苯基)-3-丁烯基1-[4,4-双(2-甲基苯基)-3-丁烯基]吡啶-3-羧酸酯溴化物（18），分别。 在-23°C下使用催化量的CuI，将吡啶盐（17/18）与THF中的PhMgCl进行非区域选择性反应，得到近似1:1的异构的4-苯基-1,4-二氢吡啶（21或22）和6-苯基-1,6-二氢吡啶（27或28）产物的混合物。 所有尝试将21/22或27/28的4,4-双(2-甲基苯基)丁基或3-丁烯基酯基水解为羧基均导致分解产物。 相反，相应的3-(2-氰乙基)酯（23,24,29,30）通过丙烯腈的β-消除反应，使用非亲核碱DBU轻松转化为相应的羧基类似物（25,26,31,32）。 4-苯基-1,4-二氢吡啶（14,25,26）和6-苯基-1,6-二氢吡啶（27/28或31/32）化合物在10^-4 M测试化合物浓度下抑制了体外对GABA的摄取，在21-44%的范围内，相对于参考药物尼佩酸（87%抑制）。 结构-活性相关性显示，二氢吡啶C-3取代基是对GABA摄取的决定因素，其效力顺序为CO2H > 2-(4,4-二甲基-4,5-二氢噁唑啉-2-基) > CO2(CH2)3CH-(邻甲苯)2和CO2(CH2)2CH=C-(邻甲苯)2。 具有C-3和（或）N-1 CO2(CH2)3CH-(邻甲苯)2取代基的化合物通常比具有CO2(CH2)2CH=C-(邻甲苯)2取代基的类似物更有效。 一般而言，1,6-二氢吡啶化合物比相应的1,4-二氢吡啶异构体更有效。 关键词：1,4-和1,6-二氢吡啶，GABA摄取抑制剂。
• Unexpected regioselective nucleophilic addition to 3-(4,4-dimethyloxazolin-2-yl)-pyridine: formation of stable 1,4-dihydropyridines
  作者：Choo Seug Giam、Albert E. Hauck

  DOI：10.1039/c39780000615

  日期：——

  The regioselective addition of organolithium reagents to 3-(4,4-dimethyloxazolin-2-yl)pyridine leads to stable 1,4-dihydropyridines.

  有机锂试剂向3-（4,4-二甲基恶唑啉-2-基）吡啶的区域选择性加成产生稳定的1,4-二氢吡啶。
• Substituted tetrahydropyridine and piperidine carboxylic acids as
  申请人：Warner-Lambert Company

  公开号：US05446057A1

  公开（公告）日：1995-08-29

  Substituted tetrahydropyridines and piperidinecarboxylic acids and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which muscarinic antagonists are useful as agents for inhibiting gastric acid release, for treating bradycardia, bronchoconstriction, urinary incontinence, atonic conditions of the gut and bladder, Parkinson's disease, dystonias, and Alzheimer's disease.

  本文描述了替代四氢吡啶和哌啶羧酸及其衍生物，以及其制备方法和制药组合物，这些毒蕈碱受体拮抗剂可用作抑制胃酸释放的药物、治疗心动过缓、支气管收缩、尿失禁、肠道和膀胱松弛症状、帕金森病、肌张力障碍和阿尔茨海默病的药物。
• Substitutions of pyridines activated by oxazolines via nucleophilic additions for metalation-alkylation
  作者：A. I. Meyers、Richard A. Gabel

  DOI：10.1021/jo00134a024

  日期：1982.6
• Hauck, Albert E.; Giam, Choo-Seng, Journal of the Chemical Society. Perkin transactions I, 1980, p. 2070 - 2076
  作者：Hauck, Albert E.、Giam, Choo-Seng

  DOI：——

  日期：——