4-fluoro-β-(4-fluorophenyl)-L-phenylalanine hydrochloride | 918625-32-8

• 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: 4-fluoro-β-(4-fluorophenyl)-L-phenylalanine hydrochloride
• 英文别名: (S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid hydrochloride；L-2-amino-3,3-bis(4-fluorophenyl)propanoic acid hydrochloride；[(1S)-1-carboxy-2,2-bis(4-fluorophenyl)ethyl]azanium;chloride
• CAS: 918625-32-8
• 化学式: C₁₅H₁₃F₂NO₂*ClH
• 分子量: 313.731
• InChiKey: KCNSBDJGJCBWAY-UQKRIMTDSA-N

物化性质

• 熔点：
  149 °C (decomp)(Solv: heptane (142-82-5))

计算性质

• 辛醇/水分配系数(LogP)：
  2.93
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  63.3
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-fluoro-β-(4-fluorophenyl)-L-phenylalanine hydrochloride 、 二碳酸二叔丁酯 在 potassium hydroxide 、 盐酸 作用下， 以 水 、 丙酮 为溶剂， 反应 1.0h， 以129 kg的产率得到(S)-2-((tert-butoxycarbonyl)amino)-3,3-bis(4-fluorophenyl)propanoic acid
  参考文献：
  名称：

  （S）-N -Boc-双（4-氟苯基）丙氨酸的大规模合成

  摘要：

  从合成12 g原理样品到超过900 kg cGMP的生产过程，描述了（S）-N -Boc-双（4-氟苯基）丙氨酸的合成方法，该合成方法是合成denagliptin的中间体。通过空间拥挤的前体2-乙酰氨基-3,3-双（4-氟苯基）丙烯酸乙酯的不对称氢化来建立手性中心。以物理形式分离各种中间体的能力很容易进行过滤，洗涤和最终纯化，这为成功的制造活动奠定了基础。

  DOI：

  10.1021/op3002855
• 作为产物：
  描述：

  4,4'-二氟二苯甲醇 在 盐酸 、 C₃₇H₃₇N₂O⁽¹⁺⁾*Br^(1-) 、 水 、 氢溴酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 5.5h， 生成 4-fluoro-β-(4-fluorophenyl)-L-phenylalanine hydrochloride
  参考文献：
  名称：

  Synthesis of 4-Fluoro-β-(4-fluorophenyl)-l-phenylalanine by an Asymmetric Phase-Transfer Catalyzed Alkylation:  Synthesis on Scale and Catalyst Stability

  摘要：

  4-Fluoro-beta-(4-fluorophenyl)-L-phenylalanine 1 was synthesized by the asymmetric phase- transfer catalyzed alkylation of tertbutyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6. Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.

  DOI：

  10.1021/op060190j

文献信息

• Production method of optically active dephenylalanine compounds
  申请人：Hamada Takayuki

  公开号：US20070032658A1

  公开（公告）日：2007-02-08

  Optically active diphenylalanine compounds may be conveniently prepared in a good yield by reacting a diphenylalanine compound represented by formula (1) with an optically active amine compound represented by formula (2) in the presence of an organic solvent to give a diastereomeric salt represented by formula (5) and then treating the diastereomeric salt under acidic conditions to give an optically active diphenylalanine compound represented by formula (3): wherein each symbol is as defined in the specification.

  光学活性的双苯丙氨酸化合物可通过在有机溶剂存在下，将式（1）表示的双苯丙氨酸化合物与式（2）表示的光学活性胺基化合物反应，得到式（5）表示的对映异构盐，然后在酸性条件下处理对映异构盐，得到式（3）表示的光学活性双苯丙氨酸化合物。其中，每个符号如规范中定义。
• Operationally convenient asymmetric synthesis of (S)-2-amino-3,3-bis-(4-fluorophenyl)propanoic acid
  作者：Vadim A. Soloshonok、Taizo Ono

  DOI：10.1016/j.jfluchem.2009.03.005

  日期：2009.6

  potassium tert-butoxide as a base. High reaction rate (1 h) chemical (>90%) and stereochemical (>95% de) outcomes of the alkylation step render this procedure reliable and operationally convenient for multi-gram synthesis of enantiomerically pure amino acid 1. Due to the simplicity of experimental procedures and commercial availability all reagents involved, this procedure can be easily reproduced in regular

  该研究表明，使用商业级叔丁醇钾作为碱，可以在乙腈为溶剂中有效地进行手性甘氨酸席夫碱3与氯化物4的烷基化反应。烷基化步骤的高反应速率（1小时）化学反应（> 90％）和立体化学反应（> 95％de）使该方法对于多克对映体纯氨基酸1的合成可靠且操作方便。由于实验程序的简单性和所有试剂的商业可得性，该程序可以在常规的生物化学实验室中轻松复制，从而可以对化合物1进行系统的生物学研究和医学应用。
• Synthesis of (S)-, (R)-, and (rac)-2-amino-3,3-bis(4-fluorophenyl)propanoic acids and an evaluation of the DPP IV inhibitory activity of Denagliptin diastereomers
  作者：Guanghui Deng、Deju Ye、Yuanyuan Li、Lingyan He、Yu Zhou、Jiang Wang、Jia Li、Hualiang Jiang、Hong Liu

  DOI：10.1016/j.tet.2008.08.097

  日期：2008.11

  The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee > 99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors. (c) 2008 Elsevier Ltd. All rights reserved.
• Synthesis of 4-Fluoro-β-(4-fluorophenyl)-<scp>l</scp>-phenylalanine by an Asymmetric Phase-Transfer Catalyzed Alkylation:  Synthesis on Scale and Catalyst Stability
  作者：Daniel E. Patterson、Shiping Xie、Lynda A. Jones、Martin H. Osterhout、Christopher G. Henry、Thomas D. Roper

  DOI：10.1021/op060190j

  日期：2007.5.1

  4-Fluoro-beta-(4-fluorophenyl)-L-phenylalanine 1 was synthesized by the asymmetric phase- transfer catalyzed alkylation of tertbutyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6. Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.
• The Large-Scale Synthesis of (<i>S</i>)-<i>N</i>-Boc-bis(4-fluorophenyl)alanine
  作者：Robert B. Appell、Lee T. Boulton、Edward D. Daugs、Matt Hansen、Christopher H. Hanson、Jerry Heinrich、Christel Kronig、Richard C. Lloyd、David Louks、Mark Nitz、Céline Praquin、James A Ramsden、Helen Samuel、Mark Smit、Matthew Willets

  DOI：10.1021/op3002855

  日期：2013.1.18

  The synthesis of (S)-N-Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various

  从合成12 g原理样品到超过900 kg cGMP的生产过程，描述了（S）-N -Boc-双（4-氟苯基）丙氨酸的合成方法，该合成方法是合成denagliptin的中间体。通过空间拥挤的前体2-乙酰氨基-3,3-双（4-氟苯基）丙烯酸乙酯的不对称氢化来建立手性中心。以物理形式分离各种中间体的能力很容易进行过滤，洗涤和最终纯化，这为成功的制造活动奠定了基础。