外消旋N,N-二乙基-2-(羟基甲基)-1-苯基-环丙烷甲酰胺 | 172016-06-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 外消旋N,N-二乙基-2-(羟基甲基)-1-苯基-环丙烷甲酰胺
• 英文名称: (1R,2S)-1-phenyl-2-(hydroxymethyl)-N,N-diethylcyclopropanecarboxamide
• 英文别名: (Z)-1-phenyl-1-diethylaminocarbonyl-2-hydroxymethylcyclopropane；(1R,2S)-N,N-Diethyl-2-(hydroxymethyl)-1-phenylcyclopropane-1-carboxamide
• CAS: 172016-06-7
• 化学式: C₁₅H₂₁NO₂
• 分子量: 247.337
• InChiKey: MAQDDMBCAWKSAZ-HIFRSBDPSA-N

物化性质

• 沸点：
  403.2±24.0 °C(Predicted)
• 密度：
  1.111±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、二氯甲烷、乙酸乙酯、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  外消旋N,N-二乙基-2-(羟基甲基)-1-苯基-环丙烷甲酰胺 在 sodium azide 、 草酰氯 、 四溴化碳 、 二甲基亚砜 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,2S)-2-[(1R)-1-azidoethyl]-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
  参考文献：
  名称：

  （+）-和（-）-米那普仑及其构象受限的类似物的合成

  摘要：

  （R）-表氯醇[（R）-5 ]与苯乙腈（6）在NaNH 2的存在下在苯中的反应生成环丙烷衍生物，其被分离为内酯4 [（1 S，2 R）-2-氧-在氰基进行碱性水解后，96％ee的1-苯基-3-氧杂双环[3,1,0]己烷]的收率为67％。化合物4容易地转化为（+）-米那普仑[（+）- 1 ]，由此证实了（+）- 1的绝对立体化学。（1 S，2 R）-1-苯基-2-[（（S）-1-氨乙基]-环丙烷-N，N-diethylcarboxamindes（2），构象受限的1的类似物，还从4合成高对映体纯度。从（S）-表氯醇[（S）-5 ]开始，还合成了它们相应的对映异构体，即（-）-米那普仑[（-）- 1 ]和ent-2 。

  DOI：

  10.1016/0040-4039(95)02221-x
• 作为产物：
  描述：

  2-(Hydroxymethyl)-1-phenylcyclopropanecarbonitrile 在 氢氧化钾 、 正丁基锂 作用下， 以 乙醇 为溶剂， 反应 17.0h， 生成 外消旋N,N-二乙基-2-(羟基甲基)-1-苯基-环丙烷甲酰胺
  参考文献：
  名称：

  Conformational Restriction by Repulsion between Adjacent Substituents on a Cyclopropane Ring:  Design and Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as Potent NMDA Receptor Antagonists

  摘要：

  Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereo selectively, the facial selectivity was reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-a and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.

  DOI：

  10.1021/jo9518056

文献信息

• Synthesis and Characterization of Process Related Impurities of (±)-Milnacipran
  作者：P. Raja Gopal、A. Christy Prabakar、ERR Chandrashekar、B. Vijaya bhaskar、P. Veera Somaiah

  DOI：10.1002/jccs.201200484

  日期：2013.6

  Milnacipran is a cyclopropane derivative, used as an anti depressant drug. During the process development of milnacipran, four process related potential impurities were detected in high performance liquid chromatography. All these impurities were identified, synthesized and subsequently characterized by their respective spectral data (IR, LC‐MS, 1H NMR, and 13C NMR) as described in this article.

  米那普仑是一种环丙烷衍生物，用作抗抑郁药。在米那普仑的工艺开发过程中，高效液相色谱法检测到四种与工艺相关的潜在杂质。如本文所述，所有这些杂质均经过鉴定，合成并随后通过其各自的光谱数据（IR，LC-MS，1 H NMR和13 C NMR）进行了表征。
• (.+-.)-(Z)-2-(Aminomethyl)-1-phenylcyclopropanecarboxamide Derivatives as a New Prototype of NMDA Receptor Antagonists
  作者：Satoshi Shuto、Hironao Takada、Daisuke Mochizuki、Ryuichi Tsujita、Yukako Hase、Shizuka Ono、Nobuko Shibuya、Akira Matsuda

  DOI：10.1021/jm00015a019

  日期：1995.7

  (+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarboxamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 mu M; 7, 13 +/- 2.1 mu M; 8, 88 +/- 1.4 mu M; 12, 10 +/- 1.2 mu M). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.

  (±)-(Z)-2-(氨基甲基)-1-苯基环丙烷-N,N-二乙基酰胺（Milnacipran，1）是一种临床有效的抗抑郁药，其及其衍生物通过改进的方法制备，并作为NMDA受体拮抗剂进行了评估。其中，Milnacipran（1）、其N-甲基衍生物（7）和N,N-二甲基衍生物（8），以及氨基甲基部分的同系物（12）均对受体显示出结合亲和力（IC50：1为6.3 ± 0.3 μM；7为13 ± 2.1 μM；8为88 ± 1.4 μM；12为10 ± 1.2 μM）。这些化合物还保护小鼠免受NMDA诱导的致死性。由于其独特的结构，这些化合物可能作为设计高效NMDA受体拮抗剂的重要原型，明确地区别于已知的受体竞争性和非竞争性拮抗剂。
• [EN] PROCESS FOR PREPARATION OF MILNACIPRAN INTERMEDIATE AND ITS USE IN PREPARATION OF PURE MILNACIPRAN<br/>[FR] MÉTHODE DE PRÉPARATION D'UN INTERMÉDIAIRE DE MILNACIPRAN ET SON UTILISATION DANS LA PRÉPARATION DE MILNACIPRAN PUR
  申请人：GLENMARK GENERICS LTD

  公开号：WO2011158249A1

  公开（公告）日：2011-12-22

  Disclosed is a process for the preparation of milnacipran intermediate, a compound of formula ΙII, and its use in the preparation of pure milnacipran.

  本发明公开了一种制备米纳西普兰中间体（化学式ΙII）的方法，以及其在制备纯米纳西普兰中的应用。
• An Efficient Synthesis of Milnacipran Hydrochloride via Reductive Amination of Aldehyde
  作者：Neha Reddy Desireddy、Arava Glory、Krishna Reddy Bhimireddy、Yadagiri Kurra、Ram Reddy

  DOI：10.1155/2017/5385843

  日期：——

  An efficient synthesis of milnacipran hydrochloride has been accomplished. The important application of this paper is the reductive amination of aldehyde to primary amine with water soluble reagents. This method provides a high yield of primary amine as the major product, reduces the number of steps, and discourages by-products.

  米那普仑盐酸盐的有效合成已经完成。本文的重要应用是使用水溶性试剂将醛还原胺化为伯胺。这种方法提供了高收率的伯胺作为主要产品，减少了步骤数量，并阻止了副产品。
• Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters
  作者：Heidi Roggen、Jan Kehler、Tine Bryan Stensbøl、Tore Hansen

  DOI：10.1016/j.bmcl.2007.02.054

  日期：2007.5

  A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantionteric excess. Structure-activity relationships for two parallel enantionteric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT. (c) 2007 Elsevier Ltd. All rights reserved.