6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine | 863513-91-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine
• 英文别名: (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine；(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine；(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine；trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'-(3'H)-pyrano[3,4-b]indol]-4-amine；trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine；1r,4r-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4b]indol]-4-amine；trans-4-(dimethylamino)-6'-fluoro-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]
• CAS: 863513-91-1
• 化学式: C₂₄H₂₇FN₂O
• 分子量: 378.49
• InChiKey: CSMVOZKEWSOFER-RQNOJGIXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.11
• 重原子数：
  28.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  28.26
• 氢给体数：
  1.0
• 氢受体数：
  2.0

安全信息

• 储存条件：
  2-8℃

制备方法与用途

CebraNOPadol 是一种同时作用于NOP和 opioid受体的激动剂，能够与人NOP、MOP、KOP 及 δ-阿片肽（DOP）受体结合，其Ki/EC50值分别为0.9 nM/13 nM、0.7 nM/1.2 nM、2.6 nM/17 nM 和 18 nM/110 nM。

反应信息

• 作为反应物：
  描述：

  6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine 在 硫酸 作用下， 以 四氢呋喃 、 水 、 丙酮 为溶剂， 反应 24.0h， 生成 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine sulfate
  参考文献：
  名称：

  [EN] SOLID FORMS OF (1R,4R)-6'-FLUORO-(N,N-DIMETHYL)-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO-[CYCLOHEXANE-1,1'-PYRANO-[3,4,B]INDOL]-4-AMINE AND SULFURIC ACID
  [FR] FORMES SOLIDES DE (1R,4R)-6'-FLUORO-(N,N-DIMÉTHYL)-4-PHÉNYL-4',9'- DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL]-4-AMINE ET D'ACIDE SULFURIQUE

  摘要：

  本发明涉及(1r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺及其硫酸盐的固态形式，例如(1r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺硫酸盐或半硫酸盐，特别是其结晶形式和/或非晶形式，包括这些固态形式的制药组合物和药物，以及这些固态形式的用途以及获得它们的过程。

  公开号：

  WO2013087591A1
• 作为产物：
  描述：

  1,4-环己二酮单乙二醇缩酮 在 盐酸 、 三氟甲磺酸三甲基硅酯 、 水 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 水 为溶剂， 反应 20.0h， 生成 6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine
  参考文献：
  名称：

  Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

  摘要：

  In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

  DOI：

  10.1021/ml500117c

文献信息

• Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol
  作者：Daniel Wachtendorf、Marc Schmidtmann、Jens Christoffers

  DOI：10.1021/acs.orglett.0c02234

  日期：2020.8.21

  decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet–Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual

  通过将二甲基氨基变为硝基，开发了一种新的合成方法来合成螺环阿片类止痛药西布兰多醇，与已建立的途径相比，该方法更为有效。基于α-硝基甲苯的α-酸度，丙烯酸酯的两次迈克尔加成反应得到无环前体化合物，其易于通过狄克曼缩合和脱羧反应转化为环己酮环化所需的环己酮衍生物。 oxa-Pictet-Spengler反应。另外一个好处是，硝基的还原提供了一种胺，可以在后期分散为羧酰胺，磺酰胺，尿素和氮-烷基同类物。用锌/甲酸/甲醛一步完成了螺环骨架上的硝基到实际标题化合物的二甲基氨基官能团的转化，收率为83％。
• Process for the preparation of (1r,4r)-6'-fluoro-(N,N-dimethyl- and N-methyl)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine
  申请人：Gruenenthal GmbH

  公开号：US20130150590A1

  公开（公告）日：2013-06-13

  A process for the preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine and (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]-indol]-4-amine or physiologically acceptable acid addition salts thereof.

  制备(1r,4r)-6′-氟-N,N-二甲基-4-苯基-4′,9′-二氢-3′H-螺[环己烷-1,1′-吡喃[3,4b]吲哚]-4-胺和(1r,4r)-6′-氟-N-甲基-4-苯基-4′,9′-二氢-3′H-螺[环己烷-1,1′-吡喃[3,4b]-吲哚]-4-胺或其生理上可接受的酸盐的制备方法。
• CRYSTALLINE (1R,4R)-6'-FLUORO-N,N-DIMETHYL-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4,B]INDOL]-4-AMINE
  申请人：Gruss Michael

  公开号：US20130012563A1

  公开（公告）日：2013-01-10

  Crystalline forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine, pharmaceutical compositions and medicaments comprising these crystalline modifications, the use of these modifications as well as a process for the enrichment of such crystalline modifications.

  (1r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4,b]吲哚]-4-胺的晶体形态，包括这些晶体修饰的药物组合物和药物，以及这些修饰的用途，以及用于富集此类晶体修饰的过程。
• [EN] PROCESS FOR THE PREPARATION OF (1R,4R)-6'-FLUORO-(N,N-DIMETHYL- AND N-METHYL)-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO-[3,4,B]INDOL]-4-AMINE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE (1R,4R)-6'-FLUORO-(N,N-DIMÉTHYL- ET N-MÉTHYL)- 4-PHÉNYL-4',9'-DIHYDRO-3'H-SPIRO[CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL]- 4-AMINE
  申请人：GRUENENTHAL GMBH

  公开号：WO2013087589A1

  公开（公告）日：2013-06-20

  The present invention relates to a process for the preparation of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4b]indol]-4-amine and (1r,4r)-6'-fluoro-N-methyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4b]- indol]-4-amine or physiologically acceptable acid addition salts thereof.

  本发明涉及一种制备(1r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺和(1r,4r)-6'-氟-N-甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4b]吲哚]-4-胺或其生理上可接受的酸盐的过程。
• [EN] SOLID FORMS OF (1R,4R)-6'-FLUORO-N,N-DIMETHYL-4-PHENYL-4',9'-DIHYDRO-3'H-SPIRO-[CYCLOHEXANE-1,1'-PYRANO[3,4,B]INDOL]-4-AMINE HYDROCHLORIDE<br/>[FR] FORMES SOLIDES DE CHLORHYDRATE DE (1R,4R)-6'-FLUORO-N,N-DIMÉTHYL-4-PHÉNYL-4',9'-DIHYDRO-3'H-SPIRO-[CYCLOHEXANE-1,1'-PYRANO[3,4,B]INDOL]-4-AMINE
  申请人：GRUENENTHAL GMBH

  公开号：WO2013087590A1

  公开（公告）日：2013-06-20

  The present invention relates to solid forms of (1 r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine hydrochloride, in particular crystalline forms and/or amorphous forms thereof, pharmaceutical compositions and medicaments comprising these solid forms, the use of these solid forms as well as to a process for obtaining them.

  本发明涉及(1 r,4r)-6'-氟-N,N-二甲基-4-苯基-4',9'-二氢-3'H-螺[环己烷-1,1'-吡喃[3,4,b]吲哚]-4-胺盐酸盐的固态形式，特别是其晶体形式和/或非晶形式、包含这些固态形式的制药组合物和药物、这些固态形式的用途以及获得它们的方法。