1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethylcyclopropanecarboxamide | 171889-06-8

• 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: 1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethylcyclopropanecarboxamide
• 英文别名: (1S,2R)-2-[(1S)-1-aminoethyl]-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
• CAS: 171889-06-8
• 化学式: C₁₆H₂₄N₂O
• 分子量: 260.379
• InChiKey: JZWQQSJMOZMVFS-DUVNUKRYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 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：

  1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethylcyclopropanecarboxamide 在 Dianion WA-30 resin (Cl^- form) 作用下， 以 甲醇 为溶剂， 生成 (1S,2R)-1-phenyl-2-<(S)-1-aminoethyl>-N,N-diethylcyclopropanecarboxamide hydrochloride
  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
• 作为产物：
  描述：

  (1S,2R)-2-Formyl-1-phenyl-cyclopropanecarboxylic acid diethylamide 在 palladium on activated charcoal 氢气 、 magnesium bromide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethylcyclopropanecarboxamide
  参考文献：
  名称：

  通过一分为二的反式构象，将格氏试剂高度立体选择性地加成到C-环丙基硝基上。PEDC的有效合成，PEDC是一种具有环丙烷结构的有效NMDA受体拮抗剂

  摘要：

  有效合成了PEDC（1），一种有效的环丙烷结构NMDA受体拮抗剂。MeMgBr通过一分为二的s-trans构象可从立体电子效应预测到其对C-环丙基硝基2的高度立体选择性加成反应，这是关键步骤。在S-反式构象的主要ç -cyclopropynitrone 2是由NOE实验表明。

  DOI：

  10.1016/s0040-4039(00)00823-6

文献信息

• Synthesis of (+)- and (−)-milnaciprans and their conformationally restricted analogs
  作者：Satoshi Shuto、Shizuka Ono、Yukako Hase、Noriko Kamiyama、Akira Matsuda

  DOI：10.1016/0040-4039(95)02221-x

  日期：1996.1

  converted to (+)-milnacipran [(+)-1], by which the absolute stereochemistry of (+)-1 was confirmed. (1S,2R)-1-Phenyl-2-[(S)-1-aminoethyl]-cyclopropane-N,N-diethylcarboxamindes (2), a conformationally restricted analog of 1, was also synthesized in high enantiomeric purity from 4. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, namely (−)-milnacipran [(−)-1] and ent-2, were

  （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 。
• Highly stereoselective addition of Grignard reagents to C-cyclopropylnitrone via the bisected s-trans conformation. An efficient synthesis of PEDC, a potent NMDA receptor antagonist having a cyclopropane structure
  作者：Yuji Kazuta、Satoshi Shuto、Akira Matsuda

  DOI：10.1016/s0040-4039(00)00823-6

  日期：2000.7

  cyclopropane structure, was achieved. The highly stereoselective addition reaction of MeMgBr to C-cyclopropylnitrone 2, via its bisected s-trans conformation which can be predicted from the stereo-electronic effects, was developed as the key step. The s-trans conformation predominant in C-cyclopropynitrone 2 was suggested by NOE experiments.

  有效合成了PEDC（1），一种有效的环丙烷结构NMDA受体拮抗剂。MeMgBr通过一分为二的s-trans构象可从立体电子效应预测到其对C-环丙基硝基2的高度立体选择性加成反应，这是关键步骤。在S-反式构象的主要ç -cyclopropynitrone 2是由NOE实验表明。
• 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。
• 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.