ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-(1H)-2-one-1-acetate | 312904-89-5

• 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: ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-(1H)-2-one-1-acetate
• 英文别名: ethyl 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-2-oxohydro-pyrazinyl}acetate；[6-Chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic Acid Ethyl Ester；ethyl 2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1-yl]acetate
• CAS: 312904-89-5
• 化学式: C₁₅H₁₅ClF₂N₄O₃
• 分子量: 372.759
• InChiKey: DCGSCXFLEBPBRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-(1H)-2-one-1-acetate 在 N-甲基吗啉 、 氢氧化钾 、 N-羟基-7-氮杂苯并三氮唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 2-[6-Chloro-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-N-(4-methoxy-pyridin-2-ylmethyl)-acetamide
  参考文献：
  名称：

  Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines

  摘要：

  Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the,modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

  DOI：

  10.1021/jm020311f
• 作为产物：
  描述：

  2-吡啶乙酸乙酯 在 10percent Pd/C sodium tetrahydroborate 、 N-氯代丁二酰亚胺 、 sodium azide 、 2,6-二叔丁基-4-甲基吡啶 、 氢气 、 双(三甲基硅烷基)氨基钾 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 7.75h， 生成 ethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-(1H)-2-one-1-acetate
  参考文献：
  名称：

  Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines

  摘要：

  Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the,modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

  DOI：

  10.1021/jm020311f

文献信息

• Development of a Scaleable Synthesis of a 3-Aminopyrazinone Acetamide Thrombin Inhibitor
  作者：Michael S. Ashwood、Ramon J. Alabaster、Ian F. Cottrell、Cameron J. Cowden、Antony J. Davies、Ulf H. Dolling、Khateeta M. Emerson、Andrew D. Gibb、David Hands、Debra J. Wallace、Robert D. Wilson

  DOI：10.1021/op0341420

  日期：2004.3.1

  addressed to provide a safe, efficient, and robust route for the preparation of multi-kilo amounts of the compound. The use of expensive and toxic reagents, notably sodium azide, TMS-cyanide, and Deoxo-Fluor, and the need for specialist equipment were overcome in the preparation of the key fluorinated intermediates 2,2-difluoro-2-(2-pyridyl)ethylamine 3 and 2-aminomethyl-3-fluoropyridine 2. With minimal isolations

  2-3-[(2,2-二氟-2-(2-吡啶基)乙基)氨基]-6-氯-2-氧代氢吡嗪基}-N-[(3-氟(2-吡啶基))的可扩展路线) 甲基]乙酰胺 1 描述了各种放大问题，以提供安全、有效和稳健的途径来制备数公斤量的化合物。在制备关键的氟化中间体 2,2-difluoro-2-(2-pyridyl) 过程中克服了使用昂贵且有毒的试剂，尤其是叠氮化钠、TMS-氰化物和 Deoxo-Fluor 以及对专业设备的需求乙胺 3 和 2-氨基甲基-3-氟吡啶 2。通过最少的分离和中间体的处理，以 36% 的总产率分离出凝血酶抑制剂 1。
• PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES
  申请人：Reddy Reguri Buchi

  公开号：US20110105753A1

  公开（公告）日：2011-05-05

  Improved process for the preparation of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide of formula (I) and its intermediates is provided.

  提供了改进的方法，用于制备式(I)的3-氟-2-吡啶甲基-3-(2,2-二氟-2-(2-吡啶基)乙基氨基)-6-氯吡嗪-2-酮-1-乙酰胺及其中间体。
• [EN] PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'UN INHIBITEUR DE THROMBINE PYRAZINONE ET SES INTERMÉDIAIRES
  申请人：DIAKRON PHARMACEUTICALS INC

  公开号：WO2011056806A1

  公开（公告）日：2011-05-12

  An improved process for the preparation of 3-fruoro-2-pyridylmethyl-3-(2,2- difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one- 1 -acetamide and its intermediates.

  一种改进的制备3-氟-2-吡啶甲基-3-(2,2-二氟-2-(2-吡啶基)乙基氨基)-6-氯吡嗪-2-酮-1-乙酰胺及其中间体的方法。
• Process for making a thrombin inhibitor
  申请人：——

  公开号：US20020103379A1

  公开（公告）日：2002-08-01

  The invention is a process for preparing 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide which comprises coupling 1 with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a coupling reagent and a base to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide.

  该发明是一种制备3-氟-2-吡啶甲基-3-(2,2-二氟-2-(2-吡啶基)乙基氨基)-6-氯吡咯烷-2-酮-1-乙酰胺的过程，包括在偶联试剂和碱的存在下，将2-氨甲基-3-氟吡啶双盐酸盐与1偶联，形成3-氟-2-吡啶甲基-3-(2,2-二氟-2-(2-吡啶基)乙基氨基)-6-氯吡咯烷-2-酮-1-乙酰胺。
• [EN] THROMBIN INHIBITORS<br/>[FR] INHIBITEURS DE LA THROMBINE
  申请人：MERCK & CO INC

  公开号：WO2002064140A1

  公开（公告）日：2002-08-22

  Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein R2 is R3 is selected from the group consisting of 1) hydrogen, 2) halogen, 3) C 1-4 alkyl, 4) C 3-7 cycloalkyl, 5) CF3, 6) OCF3, 7) C 1-4 alkoxy, and 8) cyano; and R12 is a 5-membered heteroaryl ring having 2, 3, or 4 heteroatoms, provided that at least 1 heteroatom is N, and at most 1 of the heteroatoms is S, said ring being unsubstituted or substituted, at any one ring atom, with CH3.

  本发明的化合物在抑制凝血酶和相关的血栓闭塞方面有用，其结构如下：或其药学上可接受的盐，其中R2和R3选自以下组：1）氢，2）卤素，3）C 1-4 烷基，4）C 3-7 环烷基，5）CF3，6）OCF3，7）C 1-4 醇基，8）氰基；R12是一个具有2、3或4个杂原子的5元杂环芳基环，其中至少1个杂原子是N，至多1个杂原子是S，所述环未取代或在任何一个环原子上用CH3取代。