氯吡格雷杂质E | 90055-68-8

• 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
• 中文名称: 氯吡格雷杂质E
• 英文名称: (+)-α-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-α-2-chlorophenylacetamide
• 英文别名: 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide；2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide
• CAS: 90055-68-8
• 化学式: C₁₅H₁₅ClN₂OS
• 分子量: 306.816
• InChiKey: SRKXAUBVRPEIQR-UHFFFAOYSA-N

物化性质

• 熔点：
  124-127 °C
• 沸点：
  471.7±45.0 °C(Predicted)
• 密度：
  1.362±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  74.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  氯吡格雷杂质E 在 左旋樟脑磺酸 、 苄基三乙基氯化铵 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 甲苯 为溶剂， 反应 73.5h， 生成 氯吡格雷
  参考文献：
  名称：

  Synthetic Improvements in the Preparation of Clopidogrel

  摘要：

  Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile and highly effective kinetic resolution of racemic clopidogrel using L-camphorsulphonic acid in toluene and has been successfully used in a 50-kg pilot test.

  DOI：

  10.1021/op700025d
• 作为产物：
  描述：

  2-bromo-2-(2-chlorophenyl)acetonitrile 在 苄基三乙基氯化铵 、 碳酸氢钠 、 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 15.0h， 生成 氯吡格雷杂质E
  参考文献：
  名称：

  Synthetic Improvements in the Preparation of Clopidogrel

  摘要：

  Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile and highly effective kinetic resolution of racemic clopidogrel using L-camphorsulphonic acid in toluene and has been successfully used in a 50-kg pilot test.

  DOI：

  10.1021/op700025d
• 作为试剂：
  描述：

  外消旋-2-(2-氯苯基)-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)乙腈 、 potassium carbonate 、 二甲基亚砜 、 双氧水 、 盐酸 在 甲醇 、 氯吡格雷杂质E 作用下， 以 水 、 甲醇 为溶剂， 反应 19.0h， 生成 氯吡格雷杂质E
  参考文献：
  名称：

  Process for preparing enantiomerically pure alpha phenyl-alpha (6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)-acetic acid derivatives

  摘要：

  一种制备公式（IV）的基本对映体纯化化合物或其药学上可接受的盐的方法，其中：R为氢或Cl烷基，X、Y和Z为任意原子或基团，包括从公式（V）的基本对映体纯化化合物中分离出一步，其中：R3是CN或C（O）NR1R2，R1和R2分别独立地是氢或C1-C4烷基，或者与C（O）NR1R2中的氮一起形成包括2-6个碳原子的环，从公式（V）的外消旋体转化为公式（IV）的基本对映体纯化化合物。

  公开号：

  US20050049415A1

文献信息

• [EN] NOVEL CRYSTALLINE POLYMORPHS OF CLOPIDOGREL<br/>[FR] POLYMORPHES CRISTALLINS DU CLOPIDOGREL
  申请人：GENERICS UK LTD

  公开号：WO2005026174A1

  公开（公告）日：2005-03-24

  The present invention relates to novel crystalline forms of the platelet aggregation inhibitor (+)-(S)-methyl-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate, clopidogrel (1), in the form of hydrogen bromide salts, identified as polymorph forms 1, 2 and 3. The present invention further relates to processes for preparing such forms, pharmaceutical compositions comprising such forms, and uses for such forms and compositions. The pharmaceutical compositions may be used, in particular, for inhibiting platelet aggregation or for treating, preventing or managing thrombosis, atherothrombosis, an atherothrombotic event, ischaemic stroke, myocardial infarction, non-Q-wave myocardial infarction, atherosclerosis, peripheral arterial disease, or unstable angina. The present invention also relates to methods of treating said disorders. Formula (1).

  本发明涉及新的血小板聚集抑制剂(+)-(S)-甲基-2-(2-氯苯基)-(6,7-二氢-4H-噻吩[3,2-c]吡啶-5-基)乙酸酯，即氯吡格雷（1）的晶体形式，以氢溴酸盐的形式存在，被鉴定为多晶形式1、2和3。本发明还涉及制备这些形式的方法、包含这些形式的药物组合物、以及这些形式和组合物的用途。这些药物组合物可以用于抑制血小板聚集，或用于治疗、预防或管理血栓形成、动脉粥样硬化性血栓形成、动脉粥样硬化性血栓事件、缺血性卒中、心肌梗死、非Q波型心肌梗死、动脉粥样硬化、周围动脉疾病或不稳定性心绞痛。本发明还涉及治疗上述疾病的方法。公式（1）。
• Preparation of Clopidogrel and Its Analogues Methyl Tetrahydrothienopyridine Acetate Compuunds
  申请人：Wang Lixin

  公开号：US20080249311A1

  公开（公告）日：2008-10-09

  The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.

  本发明揭示了一种使用卤代苯基乙腈（VIII）作为起始材料和四氢噻吡啶乙腈（IV）、四氢噻吡啶醋酸酯（V）作为关键中间体，进一步利用动力学分辨制备光学活性的氯吡格雷和化合物的制备方法。本发明的氯吡格雷是一种新型高效且安全的抑制血小板聚集的药物。该发明应用了系统技术对不需要的光学活性对映异构体进行消旋，回收和再利用分辨剂等，具有更大的经济优势，适用于商业规模的工业生产。其中：X代表氢、氟、氯、溴或碘原子，M代表碱金属离子。
• Process to prepare clopidogrel
  申请人：CADILA HEALTHCARE LIMITED

  公开号：US20020177712A1

  公开（公告）日：2002-11-28

  The present invention relates to a process for the preparation of thieno[3,2-c]pyridine derivatives having pharmacologically significant anti-aggregating and anti-thrombotic properties.

  本发明涉及一种制备具有药理学上重要的抗聚集和抗血栓性质的噻吩[3,2-c]吡啶衍生物的方法。
• [EN] PROCESS FOR PREPARING CLOPIDOGREL<br/>[FR] PROCEDE DE PREPARATION DE CLOPIDOGREL
  申请人：CADILA HEALTHCARE LTD

  公开号：WO2002059128A2

  公开（公告）日：2002-08-01

  The present invention discloses a process for the preparation of thieno[3,2-c]pyridine derivatives of general formula (I), in either racemic or optically active (+) or (-) forms and their salts, wherein X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. The present invention also describes a process for preparing the compounds of general formula (II), in either racemic or optically active (+) or (-) forms and their salts, where X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine. The compounds represented by formulae (I) and (II) have one asymmetric carbon and hence, the optically active compounds of formula (I) or of formula (ii), may be obtained either by resolving the racemic intermediate/final product or using an optically active intermediate. The compounds of the invention are pharmacologically active and have significant anti-aggregating and anti-thrombotic properties.

  本发明公开了一种制备一般式（I）的噻吩[3,2-c]吡啶衍生物的过程，可以是外消旋或光学活性（+）或（-）形式及其盐，其中苯环上的取代基X表示氢或卤素原子，例如氟、氯、溴或碘。本发明还描述了一种制备一般式（II）的化合物的过程，可以是外消旋或光学活性（+）或（-）形式及其盐，其中苯环上的取代基X表示氢或卤素原子，例如氟、氯、溴或碘。公式（I）和公式（II）所表示的化合物具有一个不对称碳，因此，公式（I）或公式（II）的光学活性化合物可以通过分离外消旋中间体/最终产物或使用光学活性中间体来获得。本发明的化合物具有药理活性，并具有显著的抗聚集和抗血栓性能。
• Novel Crystalline Polymorphs of Clopidogrel
  申请人：Arul Ramakrishnan

  公开号：US20070281964A1

  公开（公告）日：2007-12-06

  The present invention relates to novel crystalline forms of the platelet aggregation inhibitor (+)-(S)-methyl-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate, clopidogrel (1), in the form of hydrogen bromide salts, identified as polymorph forms 1, 2 and 3. The present invention further relates to processes for preparing such forms, pharmaceutical compositions comprising such forms, and uses for such forms and compositions. The pharmaceutical compositions may be used, in particular, for inhibiting platelet aggregation or for treating, preventing or managing thrombosis, atherothrombosis, an atherothrombotic event, ischaemic stroke, myocardial infarction, non-Q-wave myocardial infarction, atherosclerosis, peripheral arterial disease, or unstable angina. The present invention also relates to methods of treating said disorders. Formula (1).

  本发明涉及一种新的板let聚集抑制剂(+)-(S)-甲基-2-(2-氯苯基)-(6,7-二氢-4H-噻吩[3,2-c]吡啶-5-基)乙酸甲酯，氯吡格雷（1）的晶体形式，以氢溴酸盐的形式存在，被鉴定为多晶形式1、2和3。本发明还涉及制备这些形式的过程、包含这些形式的制药组合物以及这些形式和组合物的用途。这些制药组合物可以用于特别是抑制血小板聚集或治疗、预防或管理血栓形成、动脉粥样硬化、动脉粥样硬化事件、缺血性卒中、心肌梗死、非Q波心肌梗死、周围动脉疾病或不稳定型心绞痛。本发明还涉及治疗上述疾病的方法。公式（1）。