3-羟基-2-氨基甲酸苯丙酯 | 25451-53-0

• 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: 3-羟基-2-氨基甲酸苯丙酯
• 中文别名: 羟基-2-苯基丙基氨基甲酸酯
• 英文名称: 2-phenyl-1,3-propanediol monocarbamate
• 英文别名: 3-hydroxy-2-phenylpropyl aminooate；monocarbamate felbamate；MCF；2-Phenyl-3-carbamoyloxy-propanol-(1)；3-Hydroxy-2-phenylpropyl carbamate；(3-hydroxy-2-phenylpropyl) carbamate
• CAS: 25451-53-0
• 化学式: C₁₀H₁₃NO₃
• 分子量: 195.218
• InChiKey: JQVQIZWJBLGVRW-UHFFFAOYSA-N

物化性质

• 熔点：
  72-74 °C
• 沸点：
  415.1±38.0 °C(Predicted)
• 密度：
  1.214±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  72.6
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• WGK Germany：
  3

反应信息

• 作为反应物：
  描述：

  3-羟基-2-氨基甲酸苯丙酯 在 戴斯-马丁氧化剂 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以62%的产率得到阿托醛
  参考文献：
  名称：

  Role of Glutathione S-Transferases A1-1, M1-1, and P1-1 in the Detoxification of 2-Phenylpropenal, a Reactive Felbamate Metabolite

  摘要：

  Felbamate has proven to be an effective therapy for treating refractory epilepsy. However, felbamate therapy has been limited due to the associated reports of hepatotoxicity and aplastic anemia. Previous research from our laboratory has proposed 2-phenylpropenal as the reactive metabolite in felbamate bioactivation and identified its mercapturates in the urine of rats and patients undergoing felbamate therapy. While the reaction between 2-phenylpropenal and GSH has been shown to occur spontaneously under physiological conditions, the potential catalysis by glutathione transferases (GST) has remained unknown. The work presented here demonstrates a role for GST in the detoxification of 2-phenylpropenal. The kinetic data show that 2-phenylpropenal is a substrate for all three isoforms tested, with a k(cat)/K-m of 0.275 + 0.035 muM(-1) s(-1) for GSTM1-1, 0.164 +/- 0.005 muM(-1) s(-1) for GSTP1-1, and 0.042 +/- 0.005 muM(-1) s(-1) for GSTA1-1. Given that electrophilic substrates such as 2-propenal have been shown to inhibit GSTs, we also examined the inhibition of GSTM1-1, GSTP1-1 and GSTA1-1 by 2-phenylpropenal. The enzyme inhibition studies demonstrate that 2-phenylpropenal inhibits GSTP1-1 and GSTM1-1. The inhibition of GSTP1-1 was completely reversible upon filtration and reconstitution in buffer containing 10 mM GSH. However, 2-phenylpropenal inhibition of GSTM1-1 was irreversible under the same conditions. The irreversible inhibition of GSTM1-1 may be important in understanding the toxicities associated with felbamate. Given that 2-phenylpropenal is both a substrate and irreversible inhibitor for GSTM1-1, GSTM1-1 represents a potential target for 2-phenylpropenal haptenization in vivo, which may in turn mediate the observed idiosyncratic reactions.

  DOI：

  10.1021/tx000141e
• 作为产物：
  描述：

  3-hydroxy-2-phenylpropyl 4-methoxybenzylcarbamate 在 ammonium cerium (IV) nitrate 作用下， 以 水 、 乙腈 为溶剂， 反应 4.0h， 以95%的产率得到3-羟基-2-氨基甲酸苯丙酯
  参考文献：
  名称：

  催化一锅氧杂环丁烷到氨基甲酸酯的转化：药物相关分子的形式合成

  摘要：

  氧杂环丁烷是药物相关合成中的多功能构建基块，可诱导性能调节作用。尽管相关的氧杂环丁烷广泛用于与二氧化碳（CO 2）偶联的化学反应中，以提供增值的商品化学品，但是尽管这些四元杂环的合成取得了新进展，但氧杂环丁烷/ CO 2的偶联仍然极为有限。在这里，我们报告了一种有效的单锅三组分反应（3CR）策略，用于偶联（取代的）氧杂环丁烷，胺和CO 2可以提供具有出色的化学选择性和高收率的各种功能化氨基甲酸酯。该过程由铝基催化剂在相对温和的条件下介导，并且已开发的催化方法可用于两种药学上相关的氨基甲酸酯的正式合成，其中3CR是关键步骤。

  DOI：

  10.1002/adsc.201500895

文献信息

• Methods for synthesis of dicarbamate compounds and intermediates in the formation thereof
  申请人：Mortko Henry

  公开号：US20060241298A1

  公开（公告）日：2006-10-26

  Disclosed is a method of making 2-substituted-2-halo-1,3-propanediols via reduction of corresponding malonate compounds. Also disclosed is a method of making 2-substituted-2-halo-1,3-dicarbamate compounds (such as halo derivatives of felbamate, including fluorofelbamate) via reduction of malonate compounds, followed by carbamoylation. Reduction of the malonate compounds is carried out using an electrophilic hydride reagent.

  公开了一种通过还原相应的丙二酸酯化合物制备2-取代-2-卤代-1,3-丙二醇的方法。还公开了一种通过还原丙二酸酯化合物，然后进行羰酰化的方法制备2-取代-2-卤代-1,3-二氨基甲酸酯化合物（如费巴酯的卤代衍生物，包括氟费巴酯）。丙二酸酯化合物的还原是使用亲电性氢化试剂进行的。
• Metabolites of felbamate; synthesis of 2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate, 2-phenyl-2-hydroxy-1,3-propanediol dicarbamate, and 2-phenyl-1,3-propanediol monocarbamate
  作者：Yong N. Chol、Norbert Kucharczyk、R.Duane Sofia

  DOI：10.1016/s0040-4020(01)88100-x

  日期：1986.1

  Three major metabolites of felbamate, namely 2-(4-hydroxyphyenyl)-1, 3-propanediol dicarbamate. [4], 2-hydroxy-2-phenyl-1,3-propanediol dicarbamat [12], and 2-phenyl-1,3-propanediol monocarbamate [17] were prepared. The first metabolite, 4, was synthesised from p-methoxy-phenylacetic acid [1] via five steps involving carboxylation, reduction, phosgenation, demethylation, and carbonation. The second

  氨基甲酸酯的三种主要代谢物，即2-（4-羟基phyenyl）-1、3-丙二醇二氨基甲酸酯。[4]制备了2-羟基-2-苯基-1，3-丙二醇二氨基甲酸酯[12]和2-苯基-1，3-丙二醇一氨基甲酸酯[17]。第一代谢物4是由对甲氧基苯乙酸[1]通过五个步骤合成的，这些步骤涉及羧化，还原，光气化，去甲基化和碳酸化。第二个化合物12是由2-苯基-1,3-丙二醇[7]通过以下五个步骤制备的；光气化，卤化，碳酸化，脱卤和氨解。第三代谢物17的合成通过以下五个步骤从7开始：甲基化，光气化，碳酸化和去甲基化。
• A Facile, One-Pot Procedure for the Preparation of 2-Phenyl-1,3-propanediol Monocarbamate, a Metabolite of Felbamate
  作者：Thomas A. Miller、Christine M. Dieckhaus、Timothy L. Macdonald

  DOI：10.1021/op990198b

  日期：2000.11.1

  A simple, one-pot procedure for the preparation of 2-phenyl-1,3-propanediol monocarbamate (MCF) has been developed. This procedure represents the most efficient method for preparing MCF published to date, and it is amenable to the large-scale laboratory production of this biologically relevant metabolite of felbamate.

  已经开发了一种简单的一锅法制备 2-苯基-1,3-丙二醇单氨基甲酸酯 (MCF)。该程序代表了迄今为止发布的制备 MCF 的最有效方法，并且适合于大规模实验室生产这种生物相关的非尔氨酯代谢物。
• Carbamate derivatives related to meprobamate
  作者：Bernard J. Ludwig、Leo S. Powell、Frank Milan Berger

  DOI：10.1021/jm00303a029

  日期：1969.5
• The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one:  A Reactive Metabolite in Felbamate Bioactivation
  作者：Christine M. Dieckhaus、Webster L. Santos、R. Duane Sofia、Timothy L. Macdonald

  DOI：10.1021/tx000139n

  日期：2001.8.1

  4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible fl-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 +/- 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one, we have sought evidence for the significance of this pathway in experimental and clinical conditions. We report here the observation of this metabolite in the urine of rats being treated with 3-hydroxy-2-phenylpropyl aminooate, the esterase-mediated metabolite of felbamate, and in the urine of patients undergoing felbamate therapy. In addition, we have shown that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is toxic to cultured cells in a time-dependent manner, most likely as a result of its decomposition to 2-phenylpropenal. Taken together, the data support the hypothesis that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one represents a "time-release" form of 2-phenylpropenal capable of traveling to distal sites from its locus of bioactivation and thereby mediates felbamate associated toxicities.