4-{4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 4-{4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one
• 英文别名: (R)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one；4-[4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one
• 化学式: C₁₄H₁₇N₃O₄
• 分子量: 291.307
• InChiKey: DEXXSYVEWAYIGZ-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  85.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-{4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one 、 6-氯吡啶-2-羧酸 在 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 8.0h， 以26%的产率得到6-chloro-N-({(5R)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)pyridine-2-carboxamide
  参考文献：
  名称：

  利伐沙班衍生物对UDP-葡萄糖醛酸转移酶（UGT）亚型的手性抑制

  摘要：

  利伐沙班是临床上用于预防和治疗血栓栓塞性疾病的口服直接因子Xa（FXa）抑制剂。利伐沙班和CYP3A4 / 5的抑制剂存在药物-药物相互作用（DDI）。这项研究旨在研究手性中心对UDP-葡萄糖醛酸糖基转移酶（UGTs）的利伐沙班及其衍生物的抑制作用。进行化学合成以获得具有不同手性中心的利伐沙班衍生物。UGT的超小体催化的4-甲基伞形酮（4-MU）葡萄糖醛酸苷化用于评估对各种UGT亚型的抑制潜力。观察到利伐沙班衍生物对UGT1A3有重大影响。手性中心对四对利伐沙班衍生物对UGT1A3活性的影响产生不同的影响，S1的抑制潜力比R1更大，但R2，R3，R4的抑制能力比S2，S3和S4强。Dixon和Lineweaver-Burk图证明了R3和R4对UGT1A3具有竞争性抑制作用。总之，本研究证明了利伐沙班衍生物对UGT1A3活性的重大影响。手性中心严重影响了利伐沙班衍生物对UGT1A3的抑制行为

  DOI：

  10.1002/chir.22505
• 作为产物：
  描述：

  4-(4-氨基苯基)吗啡啉-3-酮 在 4-二甲氨基吡啶 、 甲胺 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 52.0h， 生成 4-{4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one
  参考文献：
  名称：

  Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939):  An Oral, Direct Factor Xa Inhibitor

  摘要：

  Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases.

  DOI：

  10.1021/jm050101d

文献信息

• PROCESS FOR PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
  申请人：MEGAFINE PHARMA (P) LTD

  公开号：US20150011756A1

  公开（公告）日：2015-01-08

  An improved process for the preparation of Rivaroxaban wherein the process substantially eliminates the potential impurities. process for preparation of Rivaroxaban which uses a novel intermediate. A process for preparing the novel intermediate which is used for the preparation of Rivaroxaban.

  一种改进的利伐沙班制备工艺，该工艺基本消除了潜在的杂质。利伐沙班制备工艺使用一种新型中间体。一种用于制备利伐沙班的新型中间体的制备工艺。
• [EN] A PROCESS FOR THE PREPARATION OF RIVAROXABAN BASED ON THE USE OF (S)-EPICHLOROHYDRIN<br/>[FR] PROCÉDÉ DE PRÉPARATION DE RIVAROXABAN FONDÉ SUR L'UTILISATION DE (S)-ÉPICHLOROHYDRINE
  申请人：ZENTIVA KS

  公开号：WO2013120465A1

  公开（公告）日：2013-08-22

  The invention relates to the stereoisomers of 4-4-[(S/R)-5-[(((aryl)methylene)- amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-ones described by the chemical formulae (S)-(9) and (R)-(9). The optical isomer of compound (9) with the (S)- configuration is industrially applicable for the manufacture of the antithrombotic drug rivaroxaban (1). The new preparation process of rivaroxaban comprises a reaction of (S)-1- chloro-3-(((aryl)methylene)amino)propan-2-ols (S)-(14) with alkyl 4-(3-oxomorpholine-4- yl)phenylcarbamates (15) providing the key intermediate (S)-(9), which is further subjected to hydrolytic deprotection and subsequent acylation, producing rivaroxaban. The commercially available (S)-epichlorohydrin has been conveniently used as the chiral building block for the production of the key intermediate.

  该发明涉及4-4-[(S/R)-5-[(((芳基)亚甲基)氨基)甲基]-2-氧代-1,3-噁唑烷-3-基]苯基}吗啡啶-3-酮的立体异构体，化学式分别为(S)-(9)和(R)-(9)。化合物(9)的光学异构体，具有(S)-构型，可用于工业制造抗凝血药利伐沙班（1）。利伐沙班的新制备过程包括(S)-1-氯-3-(((芳基)亚甲基)氨基)丙烷-2-醇(S)-(14)与烷基4-(3-氧代吗啡啶-4-基)苯基氨甲酸酯(15)发生反应，得到关键中间体(S)-(9)，随后经水解去保护和酰化反应，制备利伐沙班。商业上可获得的(S)-环氧氯丙烷已方便地用作生产关键中间体的手性构建块。
• [EN] PROCESS FOR THE PREPARATION OF RIVAROXABAN<br/>[FR] PROCÉDÉ DE PRÉPARATION DU RIVAROXABAN
  申请人：CIPLA LTD

  公开号：WO2016030669A1

  公开（公告）日：2016-03-03

  The present invention relates to an environmentally friendly process for preparing rivaroxaban. The present invention provides a process for preparing rivaroxaban of formula I, the process comprising: reacting a compound of formula VI with a base in the presence of a solvent to form a compound of formula VII; and condensing the compound of formula VII with a compound of formula VIII or a compound of formula IX in the presence of a solvent to prepare rivaroxaban of formula I, wherein the solvent used in both steps comprises water.

  本发明涉及一种环保的制备利伐洛班的过程。本发明提供了一种制备利伐洛班的方法，该方法包括：在溶剂存在的条件下，将化合物VI与碱反应以形成化合物VII；并在溶剂存在的条件下，将化合物VII与化合物VIII或化合物IX缩合以制备利伐洛班的方法，其中两个步骤中使用的溶剂均包括水。
• Process for the Preparation of Rivaroxaban
  申请人：Cipla Limited

  公开号：US20170267669A1

  公开（公告）日：2017-09-21

  The present invention relates to an environmentally friendly process for preparing rivaroxaban. The present invention provides a process for preparing rivaroxaban of formula I, the process comprising: reacting a compound of formula VI with a base in the presence of a solvent to form a compound of formula VII; and condensing the compound of formula VII with a compound of formula VIII or a compound of formula IX in the presence of a solvent to prepare rivaroxaban of formula I, wherein the solvent used in both steps comprises water.

  本发明涉及一种环保的制备利伐沙班的方法。本发明提供了一种制备式I利伐沙班的方法，该方法包括：在溶剂存在下，将式VI化合物与碱反应形成式VII化合物；并在溶剂存在下，将式VII化合物与式VIII化合物或式IX化合物缩合，制备出式I利伐沙班，其中在两个步骤中使用的溶剂均为水。
• PROCESS FOR THE PREPARATION OF A RIVAROXABAN AND INTERMEDIATES FORMED IN SAID PROCESS
  申请人：Sipos Eva

  公开号：US20140142303A1

  公开（公告）日：2014-05-22

  The invention relates to a process for the preparation of 5-chloro-N-((5-S)-2-oxo3-[4-(3-oxo-morj)holine-4-yl)-phenyl]-1,3-oxazolidine-5-yl}-methyl) thiophen-2-carboxamide having the INN rivaroxaban. The process is characterized by the reactions according to claim 1 . The invention also relates to intermediates formed in the above process.

  本发明涉及一种制备5-氯-N-((5-S)-2-氧代3-[4-(3-氧代-morj)holine-4-基)-苯基]-1,3-噁唑烷-5-基}-甲基)噻吩-2-羧酰胺的方法，该化合物为INN利伐沙班。该方法的特征在于根据权利要求1所述的反应。本发明还涉及在上述过程中形成的中间体。