(R)-5,6,6a,7-四氢-6-丙基-4H-二苯并[去,g]喹啉-2,10,11-三醇氢溴酸盐 | 79640-85-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 阿朴菲
• 中文名称: (R)-5,6,6a,7-四氢-6-丙基-4H-二苯并[去,g]喹啉-2,10,11-三醇氢溴酸盐
• 英文名称: R(-)-2,10,11-trihydroxy-N-propylnoraporphine hydrobromide
• 英文别名: R(−)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide；(6aR)-6-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,10,11-triol;hydrobromide
• CAS: 79640-85-0
• 化学式: BrH*C₁₉H₂₁NO₃
• 分子量: 392.293
• InChiKey: KIAIFHTWTMKEDI-XFULWGLBSA-N

物化性质

• 熔点：
  203-206 °C
• 溶解度：
  DMSO（少许）、甲醇（少许）、水（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.91
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  63.9
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-5,6,6a,7-四氢-6-丙基-4H-二苯并[去,g]喹啉-2,10,11-三醇氢溴酸盐 在 sodium hydroxide 、 氨 、 lithium 作用下， 以 二甲基亚砜 为溶剂， 反应 5.5h， 生成 R(-)-2,10-dihydroxy-N-n-propylnoraporphine hydrochloride
  参考文献：
  名称：

  （R）-1,2,11-三羟基-，（R）-2,11-和（R）-2,10-二羟基紫杉酚的合成-非天然存在的紫杉碱生物碱是由普卡特碱和蒂巴因合成的

  摘要：

  （合成- [R）-2,10- dihydroxyaporphine（3A），（- [R）-2,10-二羟基NN -propylnoraporphine（图3b从蒂巴因）和（- [R）-2,11-dihydroxyaporphine（7），和1个据报道，来自pukateine的，2,11-三羟基aporphine （9）。用甲磺酸将蒂巴因和诺拜恩碱重排为1a和1b，随后进行N-丙基化得到1b。1a，1b的四唑分解和2a和2b的氢解在乙酸中的Pd / C上，随后用氢溴酸（48％）进行O-去甲基化反应，生成3a和3b。R（-）-2,11-二羟基aporphine （7）是通过锂/氨水还原pukateine制备的。（R）-1,2,11-三羟基磷灰石（9）是通过普卡特碱与三溴化硼在二氯甲烷中的反应合成的。

  DOI：

  10.1002/jhet.5570280713
• 作为产物：
  描述：

  N-n-propylnormorphothebaine 在 氢溴酸 作用下， 以70%的产率得到(R)-5,6,6a,7-四氢-6-丙基-4H-二苯并[去,g]喹啉-2,10,11-三醇氢溴酸盐
  参考文献：
  名称：

  Aporphines. 36. Dopamine receptor interactions of trihydroxyaporphines. Synthesis, radioreceptor binding, and striatal adenylate cyclase stimulation of 2,10,11-trihydroxyaporphines in comparison with other hydroxylated aporphines

  摘要：

  The presence of the A ring of aporphines and the addition of substituents to it and to other portions of the aporphine ring systems can extend explorations of the dimensions and other characteristics of the dopamine receptors. Accordingly, the synthesis and some physical and pharmacological properties of a series of (-)-2,10,11-trihydroxyaporphines (3a-g) are described. Structure-activity relationships among mono-, di-, and trihydroxyaporphines were evaluated against the high-affinity (nanomolar) binding of [3H]apomorphine (APO) and [3H]spiroperidol (SPR) with a subcellular fraction (P4) of caudate nucleus from bovine brain. In addition, DA-sensitive adenylate cyclase activity was evaluated in homogenates of rat brain striatal tissue. The rank order of displacement of [3H]APO by potent aporphines (IC50 less than or equal to 30 nM) correlated approximately with their ability to stimulate cyclic AMP synthesis. Potency orders against two ligands were dissimilar; for example, increasing the size of N6-alkyl substituents increased potency vs. [3H]SPR but not vs. [3H]APO binding. Moreover, [3H]SPR binding correlated poorly with cyclase activity or [3H]APO binding, suggesting a closer relationship of [3H]APO binding to dopamine-sensitive adenylate cyclase activity.

  DOI：

  10.1021/jm00144a014

文献信息

• Aporphines. 34. (-)-2,10,11-Trihydroxy-N-n-propylnoraporphine, a novel dopaminergic aporphine alkaloid with anticonvulsant activity
  作者：J. L. Neumeyer、S. J. Law、B. Meldrum、G. Anlezark、K. J. Watling

  DOI：10.1021/jm00139a027

  日期：1981.7

  (-)-2,10,11-Trihydroxy-N-n-propylnoraporphine (TNPA,2c) has been synthesized from thebaine (3a), via northebaine (3b), normorphothebaine (2a), and alkylation to the N-propyl derivative 2b. O-Demethylation gave the desired product 2c. Compound 2c showed activity comparable to its 10,11-dihyroxy counterpart (NPA, 1b) on the stimulation of dopamine-sensitive adenylate cyclase in carp retinal homogenates. The evaluation of 2c on audiogenic seizures in mice, in the protection against paroxysimal EEG and myoclonic response to photic stimulation in the baboon, revealed a similar pharmacological profile in comparison to NPA and apomorphine, with TNPA showing a prolonged duration of action in abolishing myoclonic response to photic stimulation in the baboon.

  (-)-2,10,11-三羟基-N-正丙基去甲阿朴啡（TNPA，2c）通过从thbaine（3a）经去甲thbaine（3b）、去甲阿扑吗啡（2a）及烷基化反应制得N-正丙基衍生物2b，再经O-去甲基化反应得到目标产物2c。化合物2c在刺激鲤鱼视网膜匀浆中多巴胺敏感的腺苷酸环化酶活性方面，与具有10,11-二羟基取代的类似物（NPA，1b）显示出相当的活性。在对小鼠听觉诱发惊厥的评估，以及对狒狒中光刺激引发的阵发性脑电图和肌阵挛反应的保护作用研究中，化合物2c与NPA和阿扑吗啡相比表现出相似的药理学特性，且TNPA在消除狒狒中光刺激引发的肌阵挛反应方面表现出更长的作用持续时间。
• A two-step one-pot radiosynthesis of the potent dopamine D₂/D₃agonist PET radioligand [¹¹C]MNPA
  作者：C. Steiger、S. J. Finnema、L. Raus、M. Schou、R. Nakao、K. Suzuki、V. W. Pike、H. V. Wikström、C. Halldin

  DOI：10.1002/jlcr.1583

  日期：2009.5.15

  (R)-(−)-2-[11C]Methoxy-N-n-propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)-(−)-2-hydroxy-10,11-acetonide-N-n-propylnoraporphine, 4) was prepared from (R)-(−)-2-hydroxy-N-n-propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two-step one-pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon-11 generated from a 10-min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC-MS/MS spectrum with those of reference 2 and (R)-(−)-10-methoxy-2,11-dihydroxy-N-n-propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.

  (R)-(-)-2-[11C]甲氧基-N-正丙基去甲吗啡（[11C]MNPA ( [11C]2)）是一种激动剂放射性配体，可用于体内 D2/D3 受体成像。在此，我们试图开发一种改进的放射性配体的放射合成方法。参考 2 由可待因开始，分九步合成，总产率约为 5%。在倒数第二个甲基化步骤中，与重氮甲烷相比，三甲基硅基重氮甲烷被证明是一种切实可行的改进。用于放射性标记的受保护前体（(R)-(-)-2-羟基-10,11-丙酮-N-正丙基去甲吗啡，4）是由(R)-(-)-2-羟基-N-正丙基去甲吗啡（1）制备的，收率为 30%。[11C]2是通过两步一步放射合成法从4制备的。第一步，用[11C]甲基三酸酯对 4 进行甲基化，放射性化学收率为定量。第二步，用盐酸和加热对儿茶酚分子进行脱保护，可获得 60-90% 的 [11C]2 ，因此[11C]三氯甲烷的总掺入率为 60-90%。在一次典型的运行中，通过对氮氢靶气进行 10 分钟质子辐照（16 MeV; 35 µA）产生的碳-11，生成了超过 1 GBq 的[11C]2。[11C]2的放射化学纯度大于99%，注入时的比放射性为901±342 GBq/µmol（n=10）。从放射性核素生产结束算起，总合成时间为 35-38 分钟。通过比较[11C]2 与参考 2 和(R)-(-)-10-甲氧基-2,11-二羟基-N-正丙基去甲吗啡的 LC-MS/MS 图谱，确认了[11C]2 的身份。Copyright © 2009 John Wiley & Sons, Ltd. All Rights Reserved.
• Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogs
  作者：Yigong Gao、Ross J. Baldessarini、Nora S. Kula、John L. Neumeyer

  DOI：10.1021/jm00168a040

  日期：1990.6

  Syntheses of (R)-(-)-2-methoxyapomorphine (R-8), its antipode S-8, and its (R)-(-)-N-n-propyl R-9 derivatives are described. The dopaminergic receptor affinities of these compounds and their 2-unsubstituted counterparts (R)-(-)-apomorphine (R(-)-APO, R-1), (S)-(+)-apomorphine (S(+)-APO, S-1), and (R)-(-)-N-n-propylnorapomorphine (R(-)-NPA, R-2), as well as those of (R)-(-)-2-chloroapomorphine (R(-)-2-Cl-APO

  描述了（R）-（-）-2-甲氧基阿扑吗啡（R-8），其对映体S-8及其（R）-（-）-Nn-丙基R-9衍生物的合成。这些化合物及其2个未取代的对应物（R）-（-）-阿扑吗啡（R（-）-APO，R-1），（S）-（+）-阿扑吗啡（S（+）- APO，S-1）和（R）-（-）-Nn-propylnorapomorphine（R（-）-NPA，R-2）以及（R）-（-）-2-chloroapomorphine（R （-）-2-Cl-APO，R-6），（R）-（-）-2-Bromoapomorphine（R（-）-2-Br-APO，R-6）的组织膜制剂为来自大鼠脑的纹状体。（R）-（-）-2-羟基-Nn-丙基norapomorphine（R（-）-2-OH-NPA，R-7）中的Nn-丙基和2-羟基或（ R）-（-）-2-甲氧基-Nn-丙基诺哌吗啡（R（-）-2-OCH3-NPA，R-9）产生的D2亲和力最高（0
• The synthesis of tritiated (R)-2-methoxy-N-n-propyl-nor-apomorphine (MNPA)
  作者：Jonas Malmquist、Susanne Olofsson、Peter Ström

  DOI：10.1002/jlcr.1448

  日期：2007.11

  A method for the preparation of [3H]-MNPA ((R)-2-methoxy-N-n-propyl-norapomorphine) has been developed addressing the regioisomer problem as well as the oxidation problem. (R)-2, 10, 11-trihydroxy-N-n-propyl-norapomorphine was protected with 10, 11-dibenzyl or 10, 11-acetonide. The pure precursor was then methylated using [3H]-methyliodide. The product was isolated after deprotection and high-pressure liquid chromatography (HPLC) purification. Ascorbic acid was used as an antioxidant in the HPLC eluent and the stock solution. Characterization of the intermediates and products with 3H- and 1H-NMR was performed. A specific activity of 3.1 TBq/mmol (83.8 Ci/mmol) and 98.9% purity was obtained. Copyright © 2007 John Wiley & Sons, Ltd.

  我们开发了一种制备 [3H]-MNPA （(R)-2-甲氧基-N-正丙基-去甲吗啡）的方法，既解决了区域异构体问题，又解决了氧化问题。(R)-2，10，11-三羟基-N-正丙基-去甲吗啡用 10，11-二苄基或 10，11-丙酮保护。然后用 [3H]-methyliodide 将纯前体甲基化。经脱保护和高压液相色谱（HPLC）纯化后，分离出产物。高压液相色谱洗脱液和储备液中使用了抗坏血酸作为抗氧化剂。利用 3H 和 1H-NMR 对中间体和产物进行了表征。得到的比活度为 3.1 TBq/mmol（83.8 Ci/mmol），纯度为 98.9%。Copyright © 2007 John Wiley & Sons, Ltd. All Rights Reserved.
• GAO, YIGONG;BALDESSARINI, ROSS J.;KULA, NORA S.;NEUMEYER, JOHN L., J. MED. CHEM., 33,(1990) N, C. 1800-1805
  作者：GAO, YIGONG、BALDESSARINI, ROSS J.、KULA, NORA S.、NEUMEYER, JOHN L.

  DOI：——

  日期：——