6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid | 959426-35-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid
• 英文别名: 6-(4-Iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid
• CAS: 959426-35-8
• 化学式: C₂₀H₁₆IN₃O₄
• 分子量: 489.269
• InChiKey: SZWSAQKATKREKA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  84.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P-1 moieties that resulted in the identification of the p-methoxyphenyl P-1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P-4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidinl-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

  DOI：

  10.1021/jm070245n
• 作为产物：
  描述：

  6-(4-碘苯基)-1-(4-甲氧基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 24.0h， 以90%的产率得到6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid
  参考文献：
  名称：

  Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P-1 moieties that resulted in the identification of the p-methoxyphenyl P-1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P-4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidinl-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

  DOI：

  10.1021/jm070245n

文献信息

• Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof
  申请人：THIRUMALAI RAJAN Srinivasan

  公开号：US20150353541A1

  公开（公告）日：2015-12-10

  The present invention provides a novel intermediate as well as novel polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound represented by the following structural formula-1 and processes for their preparation.

  本发明提供了一种新的中间体以及新的多形态结构的1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酰胺化合物，其化学结构如下所示，并提供了其制备方法。
• [EN] A METHOD OF PREPARING APIXABAN<br/>[FR] PROCÉDÉ DE PRÉPARATION D'APIXABAN
  申请人：ZENTIVA KS

  公开号：WO2014075648A1

  公开（公告）日：2014-05-22

  The object of the present solution provides a method preparing apixaban of formula (I) in which ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4- c]pyridine-3-carboxylate of formula (III) is reacted with piperidin-2-one of formula (IV) in the presence of a base and a ligand and under catalysis by copper or by copper (II) ions, wherein a phosphoric acid salt is used as the base and an amine from the group of 1,2-diamines is used as the ligand in an aprotic solvent, and ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1- piperidin-1-yl)phenyl] -4, 5,6,7-tetrahydro-1H-pyrazol-[3,4-c]pyridine-3-carbvoxylate is prepared, which is converted, by reaction with ammonia in a suitable solvent, to apixaban of formula (I), which is isolated and optionally crystallized.

  本解决方案的目的是提供一种制备化合物apixaban的方法，其中以式(I)的乙酸6-(4-碘苯基)-1-(4-甲氧基苯基)-7-氧代-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯的式(III)与式(IV)的哌啶-2-酮在碱和配体的存在下，通过铜或铜(II)离子的催化反应，其中磷酸盐被用作碱，1,2-二胺类化合物被用作配体，在无极性溶剂中制备了乙酸1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代-1-哌啶-1-基)苯基]-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶-3-羧基乙酸酯，通过与适当溶剂中的氨反应，将其转化为式(I)的apixaban，然后对其进行分离和可选择结晶。
• 1, 4, 5, 6-TETRAHYDROPYRAZOLO- 3, 4-C]-PYRID IN-7-ONES AS FACTOR XA INHIBITORS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP1379245A1

  公开（公告）日：2004-01-14
• EP1379245A4
  申请人：——

  公开号：EP1379245A4

  公开（公告）日：2006-07-26
• US9718779B2
  申请人：——

  公开号：US9718779B2

  公开（公告）日：2017-08-01