恶泼西汀丁二酸盐; (2S)-2-[(S)-(2-乙氧基苯氧基)苯甲基]吗啉丁二酸盐 | 635724-55-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 恶泼西汀丁二酸盐; (2S)-2-[(S)-(2-乙氧基苯氧基)苯甲基]吗啉丁二酸盐
• 中文别名: 恶泼西汀丁二酸盐；恶泼西汀丁二酸盐;(2S)-2-[(S)-(2-乙氧基苯氧基)苯甲基]吗啉丁二酸盐；(2S)-2-[(S)-(2-乙氧基苯氧基)苯甲基]吗啉丁二酸盐
• 英文名称: (2S,3S)-reboxetine succinate
• 英文别名: (S,S)-reboxetine succinate；(2S,3S)-2-[α-(2-ethoxyphenoxy)benzyl]morpholine succinate；(2S,3S)-2-[α-(2-ethoxyphenoxy)benzyl]morpholine succinate (2S, 3S)-Reboxetine Succinate；Esreboxetine succinate；butanedioic acid;(2S)-2-[(S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine
• CAS: 635724-55-9
• 化学式: C₄H₆O₄*C₁₉H₂₃NO₃
• 分子量: 431.486
• InChiKey: YXZTUOWIYOESGT-HLRBRJAUSA-N

物化性质

• 熔点：
  149-152 °C

计算性质

• 辛醇/水分配系数(LogP)：
  3.13
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  泼西汀 在 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 生成 恶泼西汀丁二酸盐; (2S)-2-[(S)-(2-乙氧基苯氧基)苯甲基]吗啉丁二酸盐
  参考文献：
  名称：

  Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture

  摘要：

  The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.

  DOI：

  10.1021/op200181f

文献信息

• Catalyst-Controlled Diastereoselection in the Hydrogenation of Heterocycloalkyl Ketones
  作者：Masaya Akashi、Noriyoshi Arai、Tsutomu Inoue、Takeshi Ohkuma

  DOI：10.1002/adsc.201100398

  日期：2011.8

  α-Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2-(4-benzoylmorpholinyl) phenyl ketone and 3-(1-tert-butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri-sec-butylborohydride as reducing agents affords

  在反应位点附近具有小的空间和电子差异的α-取代的手性酮是难以以高非对映选择性还原的底物。使用硼氢化钠，硼氢化锌和三仲丁基硼氢化钾作为还原剂，对2-（4-苯甲酰基吗啉基）苯基酮和3-（1-叔丁氧基羰基哌啶基）苯基酮进行金属氢化物还原，可制得顺式和反式醇比例低于80:20。这些酮用的RuCl的催化剂体系的加氢2（BIPHEP）（DMEN）和氢叔在2-丙醇结果丁醇顺选择性≥99：1的醇[BIPHEP = 2,2'-双（二苯基膦基）联苯，DMEN = N，N-二甲基乙二胺]。非对映选择性的显着差异表明该氢化反应中的立体选择主要由催化剂反应场的结构（“催化剂控制的非对映选择性”）调节，而不是由底物的内部立体控制。该化学是通过动态动力学拆分用的RuCl施加到不对称氢化2 - [（小号）-BINAP] [（[R）-DMAPEN] /钾叔-丁氧化物催化剂[BINAP = 2,2'-双（二苯基膦基）-1,1'-联萘基，DMAPEN
• Process Development for (<i>S,S</i>)-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation
  作者：Kevin E. Henegar、Mateusz Cebula

  DOI：10.1021/op700007g

  日期：2007.5.1

  racemate as the (−)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol was developed. (R,R)-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated

  甲磺酸瑞波西汀是一种选择性的去甲肾上腺素摄取抑制剂（NRI），目前以消旋体形式销售。正在评估瑞波西汀的（S，S）对映异构体用于神经性疼痛和多种其他适应症的治疗。（S，S）-瑞波西汀通常是通过将外消旋物拆分为（-）-扁桃酸盐而制备的，这是一种固有的低效方法。开发了一种手性合成方法，该方法从肉桂醇的Sharpless不对称环氧化开始，生成（R，R）-苯基缩水甘油。使（R，R）-苯基缩水甘油与2-乙氧基苯酚反应而未分离，得到4通过直接结晶分离。研究了不对称环氧化的关键工艺变量。（R，S）-4到瑞波西汀的转化使外消旋合成与简化和优化的加工条件平行。（S，S）-瑞波西汀游离碱直接转化为琥珀酸盐，无需分离为甲磺酸盐。
• Method for the preparation of aryl ethers
  申请人：Cebula Mateusz

  公开号：US20050187388A1

  公开（公告）日：2005-08-25

  The invention provides a method of preparing a compound of formula (I): wherein R, R 1 , n and m are as defined herein, or a pharmaceutically acceptable salt thereof.

  该发明提供了一种制备式(I)化合物的方法：其中R、R1、n和m如本文所定义，或其药用可接受的盐。
• [EN] PHARMACEUTICAL SALTS OF REBOXETINE<br/>[FR] SELS PHARMACEUTIQUES DE REBOXETINE
  申请人：PHARMACIA ITALIA SPA

  公开号：WO2003106441A1

  公开（公告）日：2003-12-24

  The present invention relates to novel crystalline, water-soluble salts of the 2S,3S enantiomer of reboxetine, which are the fumarate and succinate salts thereof, to a process for their preparation, to their utility in therapy and to pharmaceutical compositions containing them.

  本发明涉及雷贝替林的2S,3S对映体的新型结晶、水溶性盐，即其富马酸盐和琥珀酸盐，以及其制备方法、在治疗中的用途以及含有它们的药物组合物。
• The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate
  作者：Georges Assaf、Graham Checksfield、Doug Critcher、Peter J. Dunn、Stuart Field、Laurence J. Harris、Roger M. Howard、Gemma Scotney、Adam Scott、Suju Mathew、Geoffrey M. H. Walker、Alexander Wilder

  DOI：10.1039/c1gc15921f

  日期：——

  The Pfizer Green Chemistry metrics program is described and exemplified with a case history involving the synthesis of (S,S)-reboxetine succinate. The initial route used a classical resolution approach and generated high levels of waste. This route was replaced by an enantiospecific synthesis which used Sharpless epoxidation chemistry, an enzymatic process to selectively protect a primary alcohol and a new efficient method of chiral morpholine construction as key steps. These improvements reduced the levels of waste produced by the synthesis by more than 90%. Detailed metrics starting from a common starting material (trans-cinnamyl alcohol) for all routes of synthesis are presented.

  辉瑞绿色化学指标项目进行了描述，并通过一个案例研究展示了(S,S)-雷博西丁琥珀酸的合成。最初的合成路径采用传统的分离方法，产生了大量废物。随后，该路径被一种对映选择性合成所取代，该合成采用了Sharpless环氧化反应、选择性保护原料醇的酶促反应以及一种新的高效手性莫菲林构建方法作为关键步骤。这些改进使得合成过程中产生的废物减少了90%以上。详细的指标从所有合成路径的共同起始原料（反式肉桂醇）出发进行了呈现。