(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine | 149655-33-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine
• CAS: 149655-33-4
• 化学式: C₁₄H₂₁NO
• 分子量: 219.327
• InChiKey: SSAWRIOQOGMDET-SMDDNHRTSA-N

物化性质

• 沸点：
  320.6±42.0 °C(Predicted)
• 密度：
  0.957±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine 在 氢氟酸 、 氢溴酸 、 碳酸氢钠 、 甲基磺酰氯 、 三乙胺 作用下， 以 溶剂黄146 、 乙腈 为溶剂， 反应 23.5h， 生成 (+)-1-(3(S)-3-hydroxy-3-cyclohexylpropyl)-3(R),4(R)-dimethyl-4-(3-hydroxyphenyl)piperidine
  参考文献：
  名称：

  Synthesis and absolute configuration of LY255582, a potent opioid antagonist

  摘要：

  DOI：

  10.1021/jo00004a056
• 作为产物：
  描述：

  (R)-4-(3-甲氧基苯基)-3-甲基-1,2,3,6-四氢吡啶 在 sodium tetrahydroborate 、 正丁基锂 、 sodium cyanoborohydride 、 氯甲酸苯酯 作用下， 以 四氢呋喃 、 甲醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 0.5h， 生成 (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine
  参考文献：
  名称：

  反式3,4-二甲基-4-芳基哌啶的首次不对称合成。

  摘要：

  报道了反式3，4-二甲基-4-芳基哌啶类阿片拮抗剂支架的首次不对称合成。C-3立体化学是通过CBS还原和衍生的烯丙基膦酸酯的立体选择性抗SN2'铜酸盐置换建立的。然后通过Suzuki偶联和反式4-甲基化将所得的乙烯基溴精制为目标化合物。该方法的扩展应允许对映体选择性地进入高度取代的哌啶环系统。

  DOI：

  10.1021/ol0713988

文献信息

• KAPPA OPIOID RECEPTOR BINDING LIGANDS
  申请人：Carroll Frank Ivy

  公开号：US20130158072A1

  公开（公告）日：2013-06-20

  Kappa opioid recep-tor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor, such as heroin or cocaine addictions.

  Kappa阿片受体拮抗剂提供了在kappa阿片受体的功能结合测定中产生显著改善的结果，并且这些拮抗剂在治疗通过结合kappa阿片受体得到改善的疾病状态中的使用，比如海洛因或可卡因成瘾。
• [EN] KAPPA OPIOID RECEPTOR BINDING LIGANDS<br/>[FR] LIGANDS DE LIAISON DE RÉCEPTEUR OPIOÏDE KAPPA
  申请人：CARROLL FRANK IVY

  公开号：WO2011090473A1

  公开（公告）日：2011-07-28

  Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor, such as heroin or cocaine addictions.

  Kappa阿片受体拮抗剂提供了在kappa阿片受体功能结合测定中获得显著改善的结果，并且这些拮抗剂在治疗通过kappa阿片受体结合而得到改善的疾病状态中的使用，例如海洛因或可卡因成瘾。
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF [[2(S)-[[4(R)-(3-HYDROXY PHENYL)-3(R), 4-DIMETHYL-1 -PIPERIDINYL]METHYL]-1 -OXO-3-PHENYLPROPYL] AMINO]ACETIC ACID DIHYDRATE<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION DE DIHYDRATE D'ACIDE [[2(S)-[[4(R)-(3-HYDROXYPHÉNYL)-3(R),4-DIMÉTHYL-1-PIPÉRIDINYL]MÉTHYL]-1-OXO-3-PHÉNYLPROPYL]AMINO]ACÉTIQUE
  申请人：MSN LABORATORIES PRIVATE LTD

  公开号：WO2017158615A1

  公开（公告）日：2017-09-21

  The present invention relates to an improved process for the preparation of [[2(S)-[[4(R)- (3 -hydroxypheny l)-3 (R),4-dimethyl- 1 -piperidinyl] methyl] - 1 -oxo- 3 -phenylpropyl] amino] acetic acid dihydrate, represented by the following structural formula:

  本发明涉及一种改进的制备[[2(S)-[[4(R)-(3-羟基苯基)-3(R),4-二甲基-1-哌啶基]甲基]-1-氧代-3-苯基丙基]氨基]乙酸二水合物的方法，其结构式如下：
• Synthesis and In Vitro Opioid Receptor Functional Antagonism of Methyl-Substituted Analogues of (3<i>R</i>)-7-Hydroxy-<i>N</i>-[(1<i>S</i>)-1-{[(3<i>R</i>,4<i>R</i>)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)
  作者：Juan Pablo Cueva、Tingwei Bill Cai、S. Wayne Mascarella、James B. Thomas、Hernán A. Navarro、F. Ivy Carroll

  DOI：10.1021/jm900756t

  日期：2009.12.10

  In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [S-35]GTP gamma S binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K-e values at the kappa receptor. The three most potent analogues were the monomethylated (3 R)-7-hydroxy-N-[(1S,2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide (8e) with K-e values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K-e = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the mu and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.
• Structure-activity relationships of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists for .mu.- and .kappa.-opioid receptors
  作者：Dennis M. Zimmerman、J. David Leander、Buddy E. Cantrell、Jon K. Reel、John Snoddy、Laurane G. Mendelsohn、Bryan G. Johnson、Charles H. Mitch

  DOI：10.1021/jm00072a001

  日期：1993.10

  A series of racemic N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines were evaluated for opioid agonist and antagonist activity at mu and kappa receptors. Several highly potent mu and kappa antagonists were discovered; however, no compounds with high selectivity for either the mu or kappa receptor were identified. Importantly, no derivative was found to have significant opioid agonist activity. Two derivatives were resolved, and the activities of the enantiomers were investigated. Only a limited stereochemical effect on opioid receptor selectivities was observed. The structure-activity relationships described establish the existence of an important lipophilic binding site distal to the nitrogen for both mu and kappa receptors and confirm the pure opioid antagonist pharmacophore nature of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine structure.