N-(2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl)-2-((1,1-dimethylethoxy)carbonylamino)essigsaeureamid | 176851-43-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl)-2-((1,1-dimethylethoxy)carbonylamino)essigsaeureamid
• 英文别名: tert-butyl (2-((2-(2,5-dimethoxyphenyl)-2-hydroxyethyl)amino)-2-oxoethyl)carbamate；1-(2',5'-dimethoxyphenyl)-2-(N-carbo-t-butoxyglycine-amido)-ethanol；tert-butyl N-[2-[[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]amino]-2-oxoethyl]carbamate
• CAS: 176851-43-7
• 化学式: C₁₇H₂₆N₂O₆
• 分子量: 354.403
• InChiKey: DRAORLAOXLROSW-UHFFFAOYSA-N

物化性质

• 沸点：
  597.7±50.0 °C(Predicted)
• 密度：
  1.172±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl)-2-((1,1-dimethylethoxy)carbonylamino)essigsaeureamid 在 盐酸 、 对甲苯磺酸 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 1.02h， 生成 N-[2-(2,5-二甲氧基苯基)-2-羟基乙基]甘氨酰胺
  参考文献：
  名称：

  Aminoalkohole, 4. Mitt.: Ein Trennverfahren zur Herstellung von enantiomerenreinem Midodrin

  摘要：

  Racemic midodrine chlorohydrate (rac-1) was N-protected to yield the racemic products rac-2a-c. These were converted into the diastereomeric O-acetals 3a-c/4a-c, which can easily be separated by chromatography. After removal of the N- and O-protective groups from 3a-b/4a-b, respectively, enantiomerically pure midodrine chlorohydrate R-1 and S-1 could be isolated.

  DOI：

  10.1007/bf00807396
• 作为产物：
  描述：

  对苯二甲醚 在 aluminum (III) chloride 、 sodium tetrahydroborate 、 一水合肼 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 N-(2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl)-2-((1,1-dimethylethoxy)carbonylamino)essigsaeureamid
  参考文献：
  名称：

  PROCESS FOR PREPARATION OF MIDODRINE AND INTERMEDIATES THEREOF

  摘要：

  该发明涉及制备米多吡啶或其药用可接受盐的过程。该发明还涉及制备米多吡啶中间体的过程。

  公开号：

  US20220144754A1

文献信息

• Organobase-Catalyzed Amidation of Esters with Amino Alcohols
  作者：Nicola Caldwell、Craig Jamieson、Iain Simpson、Tell Tuttle

  DOI：10.1021/ol400987p

  日期：2013.5.17

  A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification of the catalytic process are described, furnishing products in 40–100% isolated yield.

  据报道，用碱介导的方法将未活化的酯与氨基醇酰胺化。描述了催化过程的优化和实例，以40-100％的分离产率提供了产品。
• Amidation of Esters with Amino Alcohols Using Organobase Catalysis
  作者：Nicola Caldwell、Peter S. Campbell、Craig Jamieson、Frances Potjewyd、Iain Simpson、Allan J. B. Watson

  DOI：10.1021/jo501929c

  日期：2014.10.3

  the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate

  报道了一种催化方案，用于未活化的酯与氨基醇衍生物的碱介导的酰胺化。对过程的机械方面的研究表明，该反应涉及初始的酯交换反应，然后是分子内的重排。该反应本质上是高度通用的，并且可以扩展至包括通过使用碳酸二甲酯合成恶唑烷酮系统。
• Transport Characteristics of a Novel Peptide Transporter 1 Substrate, Antihypotensive Drug Midodrine, and Its Amino Acid Derivatives
  作者：Masahiro Tsuda、Tomohiro Terada、Megumi Irie、Toshiya Katsura、Ayumu Niida、Kenji Tomita、Nobutaka Fujii、Ken-ichi Inui

  DOI：10.1124/jpet.106.102830

  日期：2006.7

  Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2′,5′-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.

  米多君是一种治疗正性低血压的口服药物。这种药物口服后几乎完全被吸收，并通过一个甘氨酸残基的裂解转化为其活性形式--1-（2′,5′-二甲氧基苯基）-2-氨基乙醇（DMAE）。肠道 H+ 偶联肽转运体 1（PEPT1）转运各种肽类药物，并已被用作通过氨基酸修饰改善吸收不良药物肠道吸收的靶分子。由于米多君符合这些要求，我们研究了米多君是否能成为 PEPT1 的底物。与注射水的卵母细胞相比，表达 PEPT1 的卵母细胞对米多君（而非 DMAE）的吸收明显增加。Caco-2细胞对米多君的吸收是饱和的，并受到各种PEPT1底物的抑制。大鼠肠道对米多君的吸收非常迅速，并且受到高亲和力 PEPT1 底物环青霉素的显著抑制，这是由 30 分钟血药浓度-时间曲线下面积和最大浓度的变化所评估的。PEPT1 可转运 DMAE 的一些氨基酸衍生物，其转运与修饰的氨基酸有关。与中性底物不同，阳离子米多君在碱性 pH 下被大量吸收，我们最近报告的 PEPT1 14 状态模型再现了这种 pH 曲线。这些研究结果表明，PEPT1 可以转运米多君，并对该药物的高生物利用度做出了贡献，因此对 DMAE 进行 Gly 修饰是 DMAE 原药的理想选择。
• SYNTHESIS OF MIDODRINE HCI FROM A NOVEL INTERMEDIATE 1-(2',5'-DIMETHOXYPHENYL)-2-AZIDOETHANONE
  申请人：Novartis AG

  公开号：EP1276711A2

  公开（公告）日：2003-01-22
• US6201153B1
  申请人：——

  公开号：US6201153B1

  公开（公告）日：2001-03-13