(1S,2R)-2-Formyl-1-phenyl-cyclopropanecarboxylic acid diethylamide | 172016-00-1

• 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)-2-Formyl-1-phenyl-cyclopropanecarboxylic acid diethylamide
• 英文别名: (1S,2R)-N,N-diethyl-2-formyl-1-phenylcyclopropane-1-carboxamide
• CAS: 172016-00-1
• 化学式: C₁₅H₁₉NO₂
• 分子量: 245.321
• InChiKey: LJTURPRUPLQPRC-DZGCQCFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  (1S5R)-1-苯基-3-氧杂双环[3.1.0]己烷-2-酮（左米那普仑中间体A） 在 lithium amide 、 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (1S,2R)-2-Formyl-1-phenyl-cyclopropanecarboxylic acid diethylamide
  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

文献信息

• Synthesis and Biological Activity of Conformationally Restricted Analogs of Milnacipran:  (1<i>S</i>,2<i>R</i>)-1-Phenyl-2-[(<i>S</i>)-1-aminopropyl]-<i>N</i>,<i>N</i>-diethylcyclopropanecarboxamide, an Efficient Noncompetitive <i>N</i>-Methyl-<scp>d</scp>-aspartic Acid Receptor Antagonist
  作者：Satoshi Shuto、Shizuka Ono、Yukako Hase、Yoshihito Ueno、Tomohiro Noguchi、Kiyonori Yoshii、Akira Matsuda

  DOI：10.1021/jm960495w

  日期：1996.1.1

  antagonist. On the basis of the cyclopropane structure of (+/-)-1, conformationally restricted analogs with different stereochemistries, namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamindes (2, 3, ent-2, and ent-3), were designed and synthesized. Among these analogs, 2a, 2b, and 2f, with (1S,2R,1'S)-configuration, were more efficient than milnacipran as NMDA receptor antagonists; these compounds

  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。
• Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides as novel NMDA receptor antagonists having a unique NMDA receptor subtype selectivity
  作者：Yuji Kazuta、Ryuichi Tsujita、Shigeo Uchino、Noriko Kamiyama、Daisuke Mochizuki、Kanako Yamashita、Yutaka Ohmori、Akitake Yamashita、Tamotsu Yamamoto、Shinich Kohsaka、Akira Matsuda、Satoshi Shuto

  DOI：10.1039/b111540p

  日期：2002.4.26

  (1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b), which is a conformationally restricted analog of the antidepressant milnacipran [(±)-1], is a new class of potent NMDA (N-methyl-D-aspartic acid) receptor antagonists. A series of analogs of 2b modified at the 1′-position were designed and synthesized starting from (R)-epichlorohydrin via the key intermediate an optically

  （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
• 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。
• 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.