(1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide | 171889-07-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide
• 英文别名: (1S,2R)-1-phenyl-[(S)-1-aminopropyl]-n,N-diethylcyclopropanecarboxamide；PPDC；(1S,2R)-2-[(1S)-1-aminopropyl]-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
• CAS: 171889-07-9
• 化学式: C₁₇H₂₆N₂O
• 分子量: 274.406
• InChiKey: LFIMCYFWWBLEGS-YQQAZPJKSA-N

物化性质

• 沸点：
  413.5±24.0 °C(Predicted)
• 密度：
  1.056±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  46.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide 在 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 15.0h， 生成 [(S)-1-((1R,2S)-2-Diethylcarbamoyl-2-phenyl-cyclopropyl)-propyl]-methyl-carbamic acid tert-butyl ester
  参考文献：
  名称：

  （1 S，2 R）-1-苯基-2-[（S）-1-氨基烷基] -N，N-二乙基环丙烷甲酰胺的合成作为具有独特NMDA受体亚型选择性的新型NMDA受体拮抗剂

  摘要：

  （1 S，2 R）-1-苯基-2-[（S）-1-氨基丙基] -N，N-二乙基环丙烷甲酰胺（2b），其为抗抑郁药米那普仑[（±）-1 ]的构象受限类似物。，是一类新的有效的NMDA（N-甲基-D-天冬氨酸）受体拮抗剂。一系列的类似物的图2b的1'-位修饰设计并合成从（起始- [R ）-环氧氯丙烷经由关键中间体的光学活性的环丙烷甲醛衍生物8使用（1小号，2 - [R）-配置。在这些类似物中，（1 S，2 R）-1-苯基-2-[（S）-1-氨基丁-3-烯基] -N，N-二乙基环丙烷甲酰胺（2i）和（1 S，2 R）-1 -苯基-2-[（S）-1-氨基丁-3-炔基] -N，N-二乙基环丙烷甲酰胺（2j）被确定为比2b更有效的NMDA受体拮抗剂。研究了2i和2j以及2b的亚型选择性，结果表明2i抑制GluRε3/ζl和GluRε4/ζl亚型的强度是GluRε1/ζl和GluRε2/ζl亚型的四倍。化

  DOI：

  10.1039/b111540p
• 作为产物：
  描述：

  ethyl (3S)-3-[(1R,2S)-2-(diethylcarbamoyl)-2-phenylcyclopropyl]-3-hydroxypropanoate 在 palladium on activated charcoal 吡啶 、 甲醇 、 4-二甲氨基吡啶 、 ammonium hydroxide 、 sodium tetrahydroborate 、 sodium azide 、 四溴化碳 、 氢气 、 双氧水 、 sodium methylate 、 三乙胺 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 205.0h， 生成 (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide
  参考文献：
  名称：

  米那普仑构象受限类似物的合成及其生物学活性：（1S，2R）-1-苯基-2-[（S）-1-氨基丙基] -N，N-二乙基环丙烷甲酰胺，一种有效的非竞争性N-甲基-D-天冬氨酸酸受体拮抗剂。

  摘要：

  我们最近证明了（+/-）-（Z）-2-（氨基甲基）-1-苯基-N，N-二乙基环丙烷甲酰胺[milnacipran，（+/-）-1]是5-羟色胺再摄取的抑制剂（5 -HT）是非竞争性NMDA受体拮抗剂。根据（+/-）-1的环丙烷结构，构象受限的类似物具有不同的立体化学，即1-苯基-2-（1-氨基烷基）-N，N-二乙基环丙烷甲酰胺（2，3，ent-2，和ent-3），进行了设计和合成。在这些类似物中，具有（1S，2R，1'S）构型的2a，2b和2f比milnacipran作为NMDA受体拮抗剂更有效。这些化合物分别在IC50 = 0.35 +/- 0.08、0.20 +/- 0.024和0.16 +/- 0.02 microM时显着抑制[3H] MK-801的结合，并阻断了电压钳型卵母细胞对NMDA的反应，超过（+/-）-1的效果。

  DOI：

  10.1021/jm960495w

文献信息

• The bisected s-trans conformation-controlled highly stereoselective addition of Grignard reagents to C-cyclopropylaldonitrone. An efficient synthesis of 1-phenyl-2-[(S )-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides, a new class of potent NMDA receptor antagonists
  作者：Yuji Kazuta、Satoshi Shuto、Hiroshi Abe、Akira Matsuda

  DOI：10.1039/b008230i

  日期：——

  stereoelectronic effects of the cyclopropane ring, by X-ray crystallographic analysis, NMR studies, and theoretical calculations. Based on these findings, the highly stereoselective addition reaction of Grignard reagents to C-cyclopropylaldonitrone 6 was developed, and the reaction was successfully used as the key step for the preparation of the NMDA receptor antagonists 1a and 1b as well as for a newly

  有效合成1-苯基-2-[（S）-1-氨基乙基]-和1-苯基-2-[（S -1-氨基丙基）-N，N-二乙基环丙烷甲酰胺[ 1a（PEDC）和1b（ PPDC）]，有效NMDA受体拮抗剂具有环丙烷结构。我们首次证明，由于C-环丙基醛基的特征性立体电子效应，C-环丙基铝亚硝基优先存在于二等分的S-反式构象中。环丙烷环， 经过 X射线晶体学分析， 核磁共振研究和理论计算。基于这些发现，高度立体选择性加成反应 的 格氏试剂到ç -cyclopropylaldonitrone 6被开发，并且将反应物成功地用作用于的制备关键步骤NMDA受体拮抗剂 1a和1b以及新设计的异丙基型同类物1c。添加的面部选择性格氏试剂可以通过试剂从预测的一分为二的反式构象受阻程度较小的底物一侧进攻来解释。这个格氏反应是通过非螯合控制途径向硝酮高度立体选择性加成的第一个例子。
• Synthesis and Biological Activity of Conformationally Restricted Analogues of Milnacipran:  (1<i>S</i>,2<i>R</i>)-1-Phenyl-2-[(<i>R</i>)-1-amino-2-propynyl]<i>-N,N-</i> diethylcyclopropanecarboxamide Is a Novel Class of NMDA Receptor Channel Blocker
  作者：Satoshi Shuto、Shizuka Ono、Hiroaki Imoto、Kiyonori Yoshii、Akira Matsuda

  DOI：10.1021/jm980238m

  日期：1998.8.1

  Conformationally restricted analogues of (+/-)-(Z)-2-aminomethyl-1-phenyl-N, N-diethylcyclopropanecarboxamide [milnacipran, (+/-)-1] were designed on the basis of its characteristic cyclopropane structure and were synthesized enantioselectively to develop efficient NMDA receptor antagonists. Among these analogues, (1S,2R)-1-phenyl-2-[(R)-1-amino-2-propynyl]- N,N-diethylcyclopropanecarboxamide (2d) had one of the most potent affinities for the receptor, with a K-i value of 0.29 mu M. The blockade of NMDA receptor channels expressed by Xenopus oocytes by 2d was investigated in detail, and 2d was identified as a new class of open channel blocker against this receptor.
• Conformational Restriction by Repulsion between Adjacent Substituents on a Cyclopropane Ring:  Design and Enantioselective Synthesis of 1-Phenyl-2-(1-aminoalkyl)-<i>N,N</i>-diethylcyclopropanecarboxamides as Potent NMDA Receptor Antagonists
  作者：Satoshi Shuto、Shizuka Ono、Yukako Hase、Noriko Kamiyama、Hironao Takada、Kanako Yamasihita、Akira Matsuda

  DOI：10.1021/jo9518056

  日期：1996.1.1

  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.
• DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS OF N-HYDROXYALKYL TETRAMETHYLCYCLOPROPANE-CARBOXAMIDE, HAVING ANTI-EPILEPTIC AND METHOD FOR THEIR PREPARATION
  申请人：Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.

  公开号：EP1487787B1

  公开（公告）日：2010-12-22