N-[5-(4-溴苯基)-6-(2-羟基乙氧基)-4-嘧啶基]-N'-丙基氨基磺酰胺 | 1393813-43-8

• 物质功能分类: 有机原料 - 氨基化合物 - 酰胺类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: N-[5-(4-溴苯基)-6-(2-羟基乙氧基)-4-嘧啶基]-N'-丙基氨基磺酰胺
• 中文别名: 马西替坦中间体
• 英文名称: N-[5-(4-bromophenyl)-6-[2-hydroxyethoxy]-4-pyrimidinyl]-N-propylsulfamide
• 英文别名: N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide；N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N’-propylsulfamide；Sulfamide, N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N'-propyl-；2-[5-(4-bromophenyl)-6-(propylsulfamoylamino)pyrimidin-4-yl]oxyethanol
• CAS: 1393813-43-8
• 化学式: C₁₅H₁₉BrN₄O₄S
• 分子量: 431.31
• InChiKey: MKPBJHFHEQSWAH-UHFFFAOYSA-N

物化性质

• 沸点：
  572.2±60.0 °C(Predicted)
• 密度：
  1.553±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于乙腈（轻微）、氯仿（轻微）、甲醇（轻微、加热）

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P264,P270,P271,P280,P301+P312,P302+P352,P304+P340,P305+P351+P338,P330,P332+P313,P337+P313,P362,P403+P233,P405,P501
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2~8℃

反应信息

• 作为反应物：
  描述：

  N-[5-(4-溴苯基)-6-(2-羟基乙氧基)-4-嘧啶基]-N'-丙基氨基磺酰胺 在 Jones reagent 作用下， 以 丙酮 为溶剂， 反应 18.0h， 以45%的产率得到马西替坦杂质7
  参考文献：
  名称：

  The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog

  摘要：

  1.The metabolism of the endothelin receptor antagonist macitentan has been characterized in bile duct-cannulated rats and dogs.2.In both species, macitentan was metabolized along five primary pathways, i.e. conjugation with glucose (M9), oxidative depropylation (M6), aliphatic hydroxylation (M7), oxidative cleavage of the ethylene glycol linker (M4) and hydrolysis of the sulfamide moiety (M3). Most of the primary metabolites underwent subsequent biotransformation including conjugation with glucuronic acid or glucose, hydrolysis of the sulfamide group or secondary oxidation of the ethylene glycol moiety.3.Though there were species differences in their relative importance, all metabolic pathways were present in rat and dog. The depropylated M6 was the only metabolite present in plasma of both species.4.Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine. Biliary excretion was the major elimination pathway, while renal elimination was of little importance.

  DOI：

  10.3109/00498254.2015.1070302
• 作为产物：
  描述：

  4-溴苯乙酸甲酯 在 potassium tert-butylate 、 sodium 、 sodium hydride 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 二甲基亚砜 、 N,N-二甲基苯胺 、 mineral oil 为溶剂， 反应 171.17h， 生成 N-[5-(4-溴苯基)-6-(2-羟基乙氧基)-4-嘧啶基]-N'-丙基氨基磺酰胺
  参考文献：
  名称：

  的发现ñ - [5-（4-溴苯基）-6- [2 - [（5-溴-2-嘧啶基）氧基]乙氧基] -4-嘧啶基] - ñ '-propylsulfamide（美西特田），一种口服活性，强效双重内皮素受体拮抗剂

  摘要：

  从波生坦（1）的结构开始，我们着手于一项药物化学程序，旨在鉴定具有高口服功效的新型有效的双重内皮素受体拮抗剂。这导致发现了一系列新的烷基磺酰胺取代的嘧啶。其中，化合物17（macitentan，ACT-064992）引起了人们的特别关注，因为它是对ET B受体具有显着亲和力的ET A的有效抑制剂，并且在高血压Dahl盐敏感性大鼠中显示出优异的药代动力学特性和高体内功效。化合物17成功完成了一项肺动脉高压的长期III期临床试验。

  DOI：

  10.1021/jm3009103

文献信息

• Improved and single-pot process for the synthesis of macitentan, an endothelin receptor antagonist, via lithium amide-mediated nucleophilic substitution
  作者：Kunal M. Jagtap、Navnath C. Niphade、Chandrashekhar T. Gaikwad、Gorakshanath B. Shinde、Raghunath B. Toche、Divyesh R. Joshi、Vijayavitthal T. Mathad

  DOI：10.1007/s00706-017-2098-2

  日期：2018.3

  AbstractAn improved, simple, efficient, and telescoped synthesis of macitentan, an endothelin receptor antagonist, starting from 5-(4-bromophenyl)-4,6-dichloropyrimidine in an overall yield of around 62% is described. Graphical abstract

  摘要描述了从5-（4-溴苯基）-4,6-二氯嘧啶开始的内皮素受体拮抗剂macitentan的改进，简单，有效和可伸缩合成，总收率约为62％。 图形概要
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF MACITENTAN<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION DE MACITENTANE
  申请人：LAURUS LABS PRIVATE LTD

  公开号：WO2017093903A1

  公开（公告）日：2017-06-08

  The present invention relates to an improved process for the preparation of macitentan and pharmaceutical acceptable salts thereof. Further present invention also relates to methylene chloride solvate of macitentan and their use in the preparation of pure macitentan.

  本发明涉及一种改进的制备马西替坦及其药用可接受盐的方法。此外，本发明还涉及马西替坦的氯甲烷溶剂结晶体及其在制备纯马西替坦中的应用。
• [EN] PROCESS FOR PREPARATION OF MACITENTAN<br/>[FR] PROCÉDÉ DE PRÉPARATION DE MACITENTAN
  申请人：SHILPA MEDICARE LTD

  公开号：WO2017191565A1

  公开（公告）日：2017-11-09

  The present invention relates to a process for the preparation of N-[5-(4-Bromophenyl)- 6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'propylsulfamide or Macitentan of Formula (I). The present invention further relates to a process for the preparation highly pure N-[5- (4-Bromophenyl)-6- [2- [(5 -bromo-2-pyrimidinyl)oxy]ethoxy] -4-pyrimidinyl] - N'propylsulfamide or Macitentan of Formula (I). Said substantially pure Macitentan is useful in the preparation of pharmaceutical composition for the treatment of cardiac disorders.

  本发明涉及一种制备N-[5-(4-溴苯基)-6-[2-[(5-溴-2-嘧啶基)氧基]乙氧基]-4-嘧啶基]-N'丙基磺酰胺或式(I)的过程。本发明还涉及一种制备高纯度N-[5-(4-溴苯基)-6-[2-[(5-溴-2-嘧啶基)氧基]乙氧基]-4-嘧啶基]-N'丙基磺酰胺或式(I)的过程。所述基本纯净的马西替坦在制备用于治疗心脏疾病的药物组合物中非常有用。
• [EN] PROCESS FOR PREPARING A PYRIMIDINE INTERMEDIATE<br/>[FR] PROCÉDÉ POUR PRÉPARER UN INTERMÉDIAIRE DE PYRIMIDINE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2015004265A1

  公开（公告）日：2015-01-15

  The present invention relates to a process for preparing a pyrimidine intermediate, namely the compound of formula I-2 or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare macitentan. Macitentan (chemical names: N-[5-(4-bromophenyl)-6-[2-[(5-bromo- 2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N'-propylsulfamide or N-[5-(4-bromophenyl)- 6- 2- [(5 -bromopyrimidin-2-yl)oxy] ethoxy } pyrimidin-4-yl] -N'-propylsulfuric diamide) is an endothelin receptor antagonist that has notably been approved by the US Food and Drug Administration and the European Commission for the treatment of pulmonary arterial hypertension. It has been first disclosed in WO 02/053557. The last step of one of the potential preparation routes described in WO 02/053557, called "Possibility A" and "Possibility B", can be summarised as shown in Scheme Al hereafter.

  本发明涉及一种制备嘧啶中间体的方法，即式I-2化合物或其盐。所述的式I-2化合物或其盐可用于制备马西替坦。马西替坦（化学名称：N-[5-(4-溴苯基)-6-[2-[(5-溴-2-嘧啶基)氧基]乙氧基]-4-嘧啶基]-N'-丙基磺酰胺或N-[5-(4-溴苯基)-6-2-[(5-溴嘧啶-2-基)氧基]乙氧基}嘧啶-4-基]-N'-丙基硫酰二胺）是一种内皮素受体拮抗剂，已获得美国食品药品监督管理局和欧洲委员会批准，用于治疗肺动脉高压。该化合物首次在WO 02/053557中披露。WO 02/053557中描述的潜在制备路线之一的最后一步，称为“可能性A”和“可能性B”，可以总结如下所示的Al方案。
• [EN] PROCESS FOR THE PREPARATION OF MACITENTAN AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE MACITENTAN ET D'INTERMÉDIAIRES DE CE DERNIER
  申请人：MEGAFINE PHARMA (P) LTD

  公开号：WO2016203489A1

  公开（公告）日：2016-12-22

  The present invention relates to an improved process for preparation of Macitentan and intermediates thereof. The present invention also relates to a novel ammonium salt of Macitentan. The present invention further relates to a process for the preparation of amorphous Macitentan.

  本发明涉及一种改进的制备马西替坦及其中间体的方法。本发明还涉及马西替坦的一种新型铵盐。本发明还涉及一种制备非晶态马西替坦的方法。