1-acetoxy-4N-phthalimidobutan-2-one | 65465-66-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 1-acetoxy-4N-phthalimidobutan-2-one
• 英文别名: 2-Oxo-4-phthalimido-1-butyl acetate；N-(4-acetoxy-3-oxo-butyl)-phthalimide；1-Acetoxy-4-phthalimido-2-butanon；4-Acetoxy-1-phthalimido-3-butanon；1H-Isoindole-1,3(2H)-dione, 2-[4-(acetyloxy)-3-oxobutyl]-；[4-(1,3-dioxoisoindol-2-yl)-2-oxobutyl] acetate
• CAS: 65465-66-9
• 化学式: C₁₄H₁₃NO₅
• 分子量: 275.261
• InChiKey: IWXLHYLXUILQPZ-UHFFFAOYSA-N

物化性质

• 熔点：
  133-134 °C(Solv: water (7732-18-5))
• 沸点：
  432.6±30.0 °C(Predicted)
• 密度：
  1.331±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  80.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-acetoxy-4N-phthalimidobutan-2-one 在 盐酸 、 水 作用下， 以 异丙醇 为溶剂， 反应 4.0h， 以80%的产率得到2-(4-Hydroxy-3-oxobutyl)-1H-isoindole-1,3(2H)-dione
  参考文献：
  名称：

  Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor

  摘要：

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.

  DOI：

  10.1021/op300012d
• 作为产物：
  描述：

  邻苯二甲酸亚胺 在 溴 、 potassium hydroxide 、 sodium t-butanolate 作用下， 以 甲醇 、 乙醇 、 乙酸乙酯 为溶剂， 反应 7.0h， 生成 1-acetoxy-4N-phthalimidobutan-2-one
  参考文献：
  名称：

  Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor

  摘要：

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.

  DOI：

  10.1021/op300012d

文献信息

• Synthesis and Histamine H1 Receptor Agonist Activity of a Series of 2-Phenylhistamines, 2-Heteroarylhistamines, and Analogs
  作者：Christian Leschke、Sigurd Elz、Monique Garbarg、Walter Schunack

  DOI：10.1021/jm00008a007

  日期：1995.4

  2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(trifluoromethyl)phenyl)histamine (2-[2-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl]ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128%). The 2-substituted histamine analogues were partial H1 receptor agonists on the endothelium-denuded isolated guinea pig aorta with

  分别由合适的酰亚胺或am和乙酸2-氧代-4-邻苯二甲酰亚胺基-1-丁酸酯制备了新的组胺衍生物，其特征是在咪唑环的C2位上有一个（取代的）芳基，杂芳基，苄基或杂芳基甲基取代基（1）。在分离的豚鼠回肠上筛选化合物作为潜在的H1受体激动剂。3-卤代2-苯基组胺（卤素= Br（35）和I（36））与组胺等价，而2-（3-（三氟甲基）苯基）组胺（2- [2-（3-（三氟甲基）苯基）-1H-咪唑-4-基乙乙胺（39）比组胺的效价明显更高（39：pD2 = 6.81，相对活性= 128％）。2-取代的组胺类似物是内皮剥脱的豚鼠主动脉上的部分H1受体激动剂，pEC50值通常小于豚鼠回肠上观察到的，但发现效价等级顺序相似。H1受体拮抗剂美吡拉明可以分别依赖浓度地阻断对豚鼠回肠和主动脉的收缩作用，从而产生美吡拉敏的KB值在纳摩尔范围内。体外化合物35和39与[3H]美吡拉敏标记的豚鼠小脑膜结合，pKi分别为6
• Histamine Analogues, XXXV: 2-Substituted Histamine Derivatives Containing Classical Moieties of H2-Antagonists - a Novel Class of H1-Agonists
  作者：Volkmar Zingel、Sigurd Elz、Walter Schunack

  DOI：10.1002/ardp.19933260306

  日期：——

  A new type of H1‐agonists resulted from the combination of the essential histamine structure with parts of H2‐antagonists. 2,4‐Disubstituted imidazole derivatives were synthesized by reaction of imidic acid methyl esters with 1,3‐dihydroxypropanone, 1,4‐dihydroxybutanone or 2‐oxo‐4‐phthalimido‐1‐butylacetate in liquid NH3. The imidazole intermediates were converted into histamine analogues by simple

  一种新型的 H1 激动剂是由必需的组胺结构与部分 H2 拮抗剂组合而成的。2,4-二取代咪唑衍生物是由亚胺酸甲酯与1,3-二羟基丙酮、1,4-二羟基丁酮或2-氧代-4-邻苯二甲酰亚胺-1-乙酸丁酯在液态NH3中反应合成的。咪唑中间体通过简单的脱保护、Gabriel 合成然后脱保护或通过腈进行侧链延伸和最终氢化转化为组胺类似物。筛选新化合物对分离的豚鼠回肠的 H1 活性和对分离的豚鼠右心房的 H2 拮抗活性。这些物质是相对较弱的 H1 激动剂和中度 H2 阻滞剂。
• Histaprodifens:  Synthesis, Pharmacological in Vitro Evaluation, and Molecular Modeling of a New Class of Highly Active and Selective Histamine H₁-Receptor Agonists
  作者：Sigurd Elz、Kai Kramer、Heinz H. Pertz、Heiner Detert、Anton M. ter Laak、Ronald Kühne、Walter Schunack

  DOI：10.1021/jm991056a

  日期：2000.3.1

  A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism

  通过将相应的亚氨酸甲酯5b与2-氧代-环戊基环合，从4,4-二苯基丁腈（4b）制备了一类新的组胺类似物，其特征是在咪唑核的2位上有一个3，3-二苯丙基取代基。在液氨中的4-邻苯二甲酰亚胺基-1-乙酸丁酯或2-氧代-1,4-丁二醇，然后进行标准反应。标题化合物分别对豚鼠回肠和内皮剥脱的主动脉的收缩性H（1）受体表现出部分激动作用，但10（组胺布洛芬; 2- [2-（3，3-二苯丙基）-1H-咪达唑-4）除外-基]乙胺），在回肠测定中是完全激动剂。虽然10与组胺（1）等价，但是甲基组蛋白（13）和二甲基组蛋白（14）的功能效价比1高出3-5（13）和2-3（14）。化合物10和13-17放松了预收缩的大鼠主动脉环（完整内皮），相对效力为3.3至28倍（与1相比），也表现出部分激动作用。激动剂的作用对选择性H（1）-受体拮抗剂美吡拉敏（pA（2）约9（几内亚猪）和pA（2）约8（大鼠主动脉）的封
• Ring-substituted histaprodifen analogues as partial agonists for histamine H1 receptors: synthesis and structure–activity relationships
  作者：S Elz

  DOI：10.1016/s0223-5234(00)00105-7

  日期：2000.1

  Thirteen racemic benzene ring-substituted analogues of histaprodifen (8a; 2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine), a novel lead for potent and selective histamine H-1-receptor agonists, have been prepared from substituted 4,4-diphenylbutyronitriles 5 via cyclization of the corresponding methyl butyrimidates 6 with 2-oxo-4-phthalimido-1-butyl acetate in liquid ammonia, followed by deprotection. Nitriles 5 were accessible by alkylation of either substituted diphenylmethanes with 3-bromopropionitrile or diethyl malonate with substituted 1-chloro-diphenylmethanes and subsequent standard reactions. The title compounds 8 displayed partial agonism on contractile H-1 receptors of the guinea-pig ileum (E-max = 2-98% relative to histamine) and, compared with the endogenous agonist, were endowed with agonist potencies of 4-92%. The meta fluorinated (gc) and meta chlorinated (8f) analogues showed the highest relative potency in this series (95% confidence Limits 85-99% and 78-102%), but did not exceed the value of the lead 8a (99-124%). Compound 8c (2-[2-[3-(3-fluorophenyl)-3-phenylpropyl]-1H-imidazol-4-yl]ethanamine) was a partial agonist at contractile H-1 receptors of the guinea-pig aorta (relative potency 154% vs. 100% for histamine) and at relaxation-mediating endothelial H-1 receptors of the rat aorta (relative potency 556% vs. 100% for histamine) and matched with the functional behaviour of 8a. Agonism observed for each compound was sensitive to blockade by the selective H-1-receptor antagonist mepyramine (pA(2) approximate to 9 (guinea-pig) and pA(2) approximate to 8 (rat aorta)). All histaprodifen analogues 8 stimulated neither histaminergic H-2/H-3, nor cholinergic M-3 receptors. They displayed only low to moderate affinity for these sites (H-2: pD'(2), < 5; H-3/M-3: pA(2) < 6). With regard to the substitution pattern on the benzene ring, there was no correlation between the histaprodifen series and the corresponding derivatives of another selective H-1-receptor agonist, viz. 2-phenylhistamine. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
• 2-Substituted histamines with G-protein-stimulatory activity
  作者：H Detert、A Hagelüken、R Seifert、W Schunack

  DOI：10.1016/0223-5234(96)88235-3

  日期：1995.1

  The cationic-amphiphilic 2-substituted histamines, 2-(3-chlorophenyl)histamine (2-[2-(3-chlorophenyl)-1H-imidazol-4-yl]ethanamine) and 2-(2-cyclohexylethyl)histamine, activate pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) of the G(i)-subfamily by a receptor-independent mechanism. We studied structure-activity relationships of 2-substituted histamine derivatives for this G-protein activation using six known and 12 newly synthesized compounds. Elongation of the alkyl chain between imidazole and the ring system enhanced the potency and efficiency of substances in activating high-affinity GTP hydrolysis, ie the enzymatic activity of G-protein alpha-subunits, in membranes of HL-60 leukemic cells. Cyclopentyl-, cyclohexyl- and norbornyl-substituted histamines were more effective and potent than phenyl-substituted histamines in mediating G-protein activation in HL-60 membranes and in activating reconstituted bovine brain G(i)/G(o)-proteins. Our data show that the chain length and the type of ring system are important determinants for receptor-independent G-protein activation by 2-substituted histamines. With respect to histamine H-1-receptors, most of the substances studied displayed weak antagonistic activity.