4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide
• 英文别名: bosentan formate monoethanolate；p-tert-butyl-N-[6-(2-formyloxyethoxy)-5-(o-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl] benzenesulfonamide；2-[6-[(4-Tert-butylphenyl)sulfonylamino]-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]oxyethyl formate
• 化学式: C₂₈H₂₉N₅O₇S
• 分子量: 579.634
• InChiKey: GYEKGEZOUPCACG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  160
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide 在 水 、 sodium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 2.0h， 以93%的产率得到波生坦
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING BOSENTAN
  [FR] PROCÉDÉ DE PRÉPARATION DE BOSENTAN

  摘要：

  本发明涉及一种在制备波生坦中有用的新型中间体，以及制备所述中间体和波生坦的方法。该发明还涉及根据本发明的方法制备的波生坦组合物及其在治疗内皮素受体介导的疾病中的应用。

  公开号：

  WO2009098517A1
• 作为产物：
  描述：

  5-(2-甲氧基苯氧基)-[2,2'-二嘧啶]-4,6(1H,5H)-二酮 在 四丁基溴化铵 、 potassium carbonate 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲苯 为溶剂， 反应 4.0h， 生成 4-[(1,1-dimethylethyl)-N-[6-(2-formyloxy)ethoxy]-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide
  参考文献：
  名称：

  Research and Development of a Second-Generation Process for Bosentan, an Endothelin Receptor Antagonist

  摘要：

  A second-generation manufacturing process from 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-(1H,5H)-dione to bosentan is based on the synthesis and deprotection of the tert-butyl ether of bosentan using available and inexpensive ethylene glycol mono-tert-butyl ether. This new strategy triggered a cascade of process improvements. Isolations are reduced from six to three, and drying operations, from five to two. Process solvents are reduced from six to two. The isolations of two sensitizers are eliminated. Toluene is used in place of methylene chloride. Two aqueous waste streams are eliminated by replacing DMF and ethylene glycol by toluene. Two methanol-isopropyl acetate recrystallizations of bosentan are replaced by the decantation of a suspension of bosentan formate monoethanolate in ethanol-toluene. Finally, the overall yield is increased from 67 to 84% and the final product purity improved from 99.3 to 99.7%.

  DOI：

  10.1021/op010234i

文献信息

• PROCESSES FOR THE PREPARATION OF BOSENTAN AND ITS INTERMEDIATES THEREOF
  申请人：Yadav Roop Singh

  公开号：US20100256371A1

  公开（公告）日：2010-10-07

  The present invention relates to processes for the preparation of bosentan and compounds that can be used as structurally novel intermediates for the synthesis thereof, and a pharmaceutical composition of the same.

  本发明涉及用于制备博瑟坦和可用作其合成的结构新型中间体的过程，以及相应的药物组合物。
• PROCESS FOR THE INTRODUCTION OF HYDROXYETHOXY SIDE CHAIN IN BOSENTAN
  申请人：Gaitonde Abhay

  公开号：US20100249162A1

  公开（公告）日：2010-09-30

  The present invention relates to an improved process for the preparation of bosentan. In particular it relates to a process for preparing bosentan substantially free from the dimer impurity of formula (II) and the 6-hydroxy impurity of formula (III). The invention also relates to a pharmaceutical composition comprising bosentan and its use in the treatment of endothelin-receptor mediated disorders.

  本发明涉及一种改进的波生坦制备过程。具体而言，它涉及一种用于制备基本不含式（II）的二聚体杂质和式（III）的6-羟基杂质的波生坦的过程。该发明还涉及一种包含波生坦的药物组合物，以及其在治疗内皮素受体介导的疾病中的用途。
• 用于制备波生坦的方法
  申请人：基因里克斯(英国)有限公司

  公开号：CN101939301A

  公开（公告）日：2011-01-05

  本发明涉及用于制备波生坦的新型中间体和用于制备所述中间体和波生坦的方法。本发明还涉及包含通过根据本发明的方法而制备的波生坦的组合物及其在治疗内皮素受体介导的障碍中的应用。
• Preparation of sulfonamides
  申请人：Roche Colorado Corporation

  公开号：US06136971A1

  公开（公告）日：2000-10-24

  The present invention provides a process for preparing 1,2-diheteroethylene sulfonamide of the formula: ##STR1## by reacting a pyrimidine monohalide of the formula: ##STR2## with a mono-protected 1,2-diheteroethylene anion of the formula M.sub.1 XCH.sub.2 CH.sub.2 YR.sub.5 and removing the protecting group, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, Z, X, Y, M, M.sub.1 and W are defined herein.

  本发明提供了一种制备式为：##STR1##的1,2-二杂乙烯磺酰胺的方法，该方法通过将式为：##STR2##的嘧啶单卤代物与式为M.sub.1 XCH.sub.2 CH.sub.2 YR.sub.5的单保护1,2-二杂乙烯负离子反应，并去除保护基，其中R.sub.1，R.sub.2，R.sub.3，R.sub.4，R.sub.5，R.sub.6，R.sub.7，R.sub.8，R.sub.9，Z，X，Y，M，M.sub.1和W在此被定义。
• [EN] PREPARATION OF SULFONAMIDES<br/>[FR] PREPARATION DE SULFONAMIDES
  申请人：HOFFMANN LA ROCHE

  公开号：WO2001055120A1

  公开（公告）日：2001-08-02

  The present invention provides a process for preparing 1, 2-diheteroethylene sulfonamide of the formula (i) by reacting a pyrimidine monohalide of the formula (ii) with a mono-protected 1, 2-diheteroethylene anion of the formula M1XCH2CH2YR5 and removing the protecting group, wherein R1 is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl; R2 is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH2COORa; and R3 is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy, or trifluoromethoxy; or R2 and R3 together can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R4 is hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, lower alkoxy, lower alkylthio, lower alkylthio-lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy, lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkoxy, lower alkylsulfinyl, lower alkylsulfonyl, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, amino, lower alkylamino, di-lower alkylamino, arylamino, aryl, arylthio, aryloxy, aryl-lower alkyl or heterocyclyl; R5 is a protecting group; R6, R7, R8 and R9 are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxy, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or R7 together with R6 or R8 can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z is O, S, ethylene, vinylene, C(=O), OCHR10, or SCHR10; R10 is hydrogen or lower alkyl; X and Y are independently O, S, or NH; M is hydrogen, an alkaline metal or an alkaline earth metal; M1 is an alkaline metal or an alkaline earth metal; and W is a halide.

  本发明提供了一种制备式（i）的1,2-二杂乙烯磺酰胺的方法，该方法通过将式（ii）的嘧啶单卤代物与式M1XCH2CH2YR5的单保护1,2-二杂乙烯负离子反应，并去除保护基，其中R1是氢、低碳基、低氧基、低硫基、卤素或三氟甲基；R2是氢、卤素、低氧基、三氟甲基或OCH2COORa；R3是氢、卤素、低碳基、低硫基、三氟甲基、环烷基、低氧基或三氟甲氧基；或R2和R3可以共同为丁二烯基、亚甲二氧基、乙二氧基或异丙基亚甲基二氧基；R4是氢、低碳基、环烷基、三氟甲基、低氧基、低硫基-低碳基、羟基-低碳基、羟基-低氧基、低氧基-低碳基、羟基-低氧基-低碳基、羟基-低氧基-低氧基、低碳基亚砜基、低碳基磺酰基、2-甲氧基-3-羟基丙氧基、2-羟基-3-苯基丙基、氨基-低碳基、低碳基氨基-低碳基、二-低碳基氨基-低碳基、氨基、低碳基氨基、二-低碳基氨基、芳基氨基、芳基、芳基硫、芳基氧、芳基-低碳基或杂环基；R5是保护基；R6、R7、R8和R9分别是氢、卤素、低碳基、三氟甲基、低氧基、低硫基、羟基、羟甲基、氰基、羧基、甲酰基、甲硫氧基基、甲磺酰基、甲磺酰氧基或低碳基氧基-羧酸酯基；或R7与R6或R8可以共同为丁二烯基、亚甲二氧基、乙二氧基或异丙基亚甲基二氧基；Z是O、S、乙烯、乙烯基、C（=O）、OCHR10或SCHR10；R10是氢或低碳基；X和Y分别是O、S或NH；M是氢、碱金属或碱土金属；M1是碱金属或碱土金属；W是卤素。