trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine
• 英文别名: trans-5,6,6a,7,8,12b-hexahydro-10,11-dimethoxybenzo[a]phenanthridine；(6aR,12bS)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine
• 化学式: C₁₉H₂₁NO₂
• 分子量: 295.381
• InChiKey: OHIPNEPFZFYAFS-VQIMIIECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 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：
  30.5
• 氢给体数：
  1
• 氢受体数：
  3

上下游信息

反应信息

• 作为反应物：
  描述：

  trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine 以73的产率得到二受体激动剂盐酸盐
  参考文献：
  名称：

  Tetrahedron 2004, 60, 4237-4242

  摘要：

  DOI：
• 作为产物：
  描述：

  (6aR,12bS)-(+)-6-((R)-α-methoxyphenylacetyl)-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine 在 三乙基硼氢化锂 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 生成 trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzophenanthridine
  参考文献：
  名称：

  Dopaminergic Benzo[a]phenanthridines: Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist

  摘要：

  Racemic trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D-1 dopamine receptor. In addition to its full D-1 agonist properties, 2 also is a good ligand for D-2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D-1 and D-2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D-1 receptor labeled by [H-3]SCH23390 (K(0.5)s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D-1 receptors expressed in transfected Ltk(-) cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC(50) of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 mu M for the (-)-enantiomer. With respect to D-2-like receptors, (+)-2 had a K-0.5 of 87.7 nM in competing with [H-3]spiperone at D-2 binding sites in rat striatal membranes versus about 1 mu M for the (-)-enantiomer. Together, these data demonstrate that both the D-1 and D-2 activities of dihydrexidine reside principally in the (GaR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D-1 receptor.

  DOI：

  10.1021/jm00041a025

文献信息

• A Novel and Efficient Synthesis of Dihydrexidine
  作者：David Nichols、Juan Cueva

  DOI：10.1055/s-0028-1083359

  日期：——

  efficient synthesis of the dopamine D1 selective full agonist dihydrexidine has been achieved in high yields and requiring no chromatographic separations via a facilitated intramolecular Henry cyclization of a (nitropropyl)benzophenone and subsequent diastereomerically selective reduction of the resulting tricyclic nitroalkene. acylations - intramolecular Henry reaction - nitroalkene - total synthesis.

  高产率地实现了多巴胺D 1选择性全激动剂二氢己定的有效合成，并且不需要通过（硝基丙基）二苯甲酮的分子内亨利环化和随后的非对映异构选择性还原得到的三环硝基烯而进行色谱分离。 酰化-分子内Henry反应-硝基烯烃-全合成。
• Protecting group directed cyclization: asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor
  作者：Rajesh Malhotra、Sagar Chakrabarti、Tushar K. Dey、Swarup Dutta、Krishna Babu Alapati、Shantanu Dutta、Subho Roy、Sourav Basu、Saumen Hajra

  DOI：10.1016/j.tet.2013.08.042

  日期：2013.10

  Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel–Crafts

  保护基团的氨基和系留ö -arene衍生自1,4-芳基-2-氨基-1-丁醇的功能升丝氨酸使然酸性条件导致非对映选择性反转下环化模式。Ñ -Boc和乙缩醛保护的氨基醇进行环化级联提供专门的顺式-dihydrexidine通过还原，其中形成C形环（异喹啉单元）之前的Friedel-Crafts环化控制的顺式-立体化学的B环的。Ñ -Cbz和ö -苄基保护直接第一架F-C环化，得到的反式-1-芳基-2-氨基四氢化萘和随后的脱保护环化形成C形环，得到二羟西汀。
• [EN] OPTICALLY ACTIVE ISOMERS OF DIHYDREXIDINE AND ITS SUBSTITUTED ANALOGS<br/>[FR] ISOMERES OPTIQUEMENT ACTIFS DE LA DIHYDREXIDINE ET DE SES ANALOGUES SUBSTITUES
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO1996002513A1

  公开（公告）日：1996-02-01

  (EN) Optically active hexahydrobenzo[$i(a)]phenanthridines of formula (I) wherein R is hydrogen or C1-C4 alkyl; R1 is hydrogen or a phenol protecting group, X is fluoro, chloro, bromo, iodo or a group of the formula OR5, and R2, R3, and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl, phenyl, fluoro, chloro, bromo, iodo, or a group -OR1 are disclosed. The method of resolving the racemic $i(trans)-hexahydrobenzo[a]phenanthridines into their component enantiomers is also disclosed. Pharmacological evidence reveals that only one of the enantiomers of a preferred phenanthridine, dihydrexidine, the (6a$i(R), 12b$i(S))-(+)-isomer, is active in binding to both D1-like and D2-like dopamine receptors. Various other compounds, compositions, and methods of using the optically active stereoisomers are likewise disclosed.(FR) L'invention concerne des hexahydrobenzo[$i(a)]phénanthridines optiquement actives de la formule (I). Dans cette formule, R est un hydrogène ou un C1-C4 alkyle; R1 est un hydrogène ou un groupe protecteur du phénol, X est un fluoro, un chloro, un bromo, un iodo ou un groupe de la formule OR5; R2, R3 et R4 sont choisis d'une manière indépendante dans le groupe constitué par l'hydrogène, C1-C4 alkyle, phényle, fluoro, chloro, bromo, iodo ou un groupe -OR1. On décrit également un procédé pour fractionner le mélange racémique de $i(trans)-hexahydrobenzo[$i(a)]phénanthridines en composants énantiomères. Les études pharmacologiques montrent qu'un seul des enantiomères d'une phénanthridine préférée, la dihydrexidine, en l'occurrence l'isomère (6a$i(R), 12b$i(S))-(+) se fixe activement simultanément aux récepteurs de la dopamine du type D1 et du type D2. On décrit également différents autres composés, ainsi que des compositions et des procédés d'utilisation des stéréoisomères optiquement actifs.

  （中文翻译）本发明涉及一种化合物，即式（I）中的光学活性六氢苯并[$i(a)]菲啶，其中R是氢或C1-C4烷基；R1是氢或苯酚保护基；X是氟、氯、溴、碘或式OR5的基团，而R2、R3和R4是独立地从羟基、C1-C4烷基、苯基、氟、氯、溴、碘或基团-OR1中选择的。本发明还公开了将外消旋的$i(trans)-六氢苯并[$i(a)]菲啶分离成其组分对映异构体的方法。药理学证据表明，优选的菲啶二氢雷克西定的两个对映异构体中，只有一个（6a$i(R), 12b$i(S))-(+)-异构体对D1型和D2型多巴胺受体都具有结合活性。本发明还公开了各种其他化合物、组合物和使用光学活性对映异构体的方法。
• A new approach for the synthesis of (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (dihydrexidine)
  作者：K. Negash、D.E. Nichols

  DOI：10.1016/0040-4039(96)01574-2

  日期：1996.9

  A novel method is reported for the synthesis of (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (dihydrexidine, 6b) employing as a key step the cyclization of the acid chloride of 3b, via decarbonylation, to the hexahydrobenzo[a]phenanthridine 4b.

  报道了一种新的方法，用于合成（±）-trans-10,11-dihydroxy-5,6,6a，7,8,12b-六氢苯并[a]菲啶（dihydrexidine，6b），这是环化的关键步骤通过脱羰，将3b的酰氯生成六氢苯并[a]菲啶4b。
• The first asymmetric synthesis of a dopamine D1 agonist, dihydrexidine, employing asymmetric conjugate addition technology
  作者：Yasutomi Asano、Mitsuaki Yamashita、Kazushige Nagai、Masami Kuriyama、Ken-ichi Yamada、Kiyoshi Tomioka

  DOI：10.1016/s0040-4039(01)01823-8

  日期：2001.11

  The first asymmetric synthesis of benzophenanthridine dopamine D1 full agonist, dihydrexidine, was accomplished employing three key processes, external chiral ligand-cont rolled conjugate addition of phenyllithium, Curtius conversion of a carboxylic group to an amino group, and finally Pictet-Spengler type cyclization completing skeleton construction. (C) 2001 Elsevier Science Ltd. All rights reserved.