Process for preparation of endothelial receptor antagonist (bosentan)

A technology of bosentan and solvent, applied in the field of preparing endothelin receptor antagonists, can solve the problems of expensive and cumbersome methods

Inactive Publication Date: 2012-04-18
SANDOZ LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the steps involved in said prior art are multiple steps, thus making the method expensive and cumbersome

Method used

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  • Process for preparation of endothelial receptor antagonist (bosentan)
  • Process for preparation of endothelial receptor antagonist (bosentan)
  • Process for preparation of endothelial receptor antagonist (bosentan)

Examples

Experimental program
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Embodiment approach

[0040] According to a preferred embodiment of the present invention, the method for preparing bosentan comprises reacting (2-methoxyphenoxy)-2,2'-bipyrimidine (compound 1) with phosphorus oxychloride to obtain 4,6-bis Chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Compound 2). This intermediate is refluxed with 4-tert-butylbenzenesulfonamide (compound 3) in the presence of a base such as alkali metal hydroxide or carbonate and solvent to give 4-tert-butyl-N-[6-chloro- 5-(2-Methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (Compound 4). The product is reacted with ethylene glycol in the presence of alkali metal amide or alkali metal hydride to obtain crude bosentan. The obtained product was purified with an organic solvent such as methanol and isopropyl acetate. This embodiment is shown in Scheme I below.

[0041]

[0042]

[0043] Process I

[0044] In embodiments of the present invention, solvents used include, but are not limited to, acetone and toluene.

[0045] B...

Embodiment 1

[0086] 5-(2-Methoxyphenyl)-2-(pyrimidin-2-yl)pyrimidine-4,6-(1H,5H)-dione from 2-cyanopyrimidine (compound 1)

[0087]900ml of methanol and 100.0g of 2-cyanopyrimidine were added at 25-30°C and stirred for 5 minutes. A solution of 5.14 g of sodium methoxide in 50.0 ml of methanol was added at 25-30° C. and stirred for 3.0 hours. The progress of the reaction was monitored by HPLC. Add 56.0 g of ammonium chloride and stir at 25-30°C for 3.0 hours. A stock solution of 221.0 g of sodium methoxide in 800.0 ml of methanol (weight - 781.0 gm) was prepared. 599.0 g of sodium methoxide was added to the reaction mass at 20-25°C. Stir at 20-25°C for 1.0 hour. The reaction was cooled to 20 °C. A stock solution of 338.50 g of DMMPM in 1.60 L of methanol was prepared (weight - 1.5475 kg). 1.216 kg of the prepared stock solution of DMMPM was added to the reactant at 20-25°C. Stir at 20-25°C for 7.0 hours. The remaining sodium methoxide stock solution in methanol (182.0 gm) from t...

Embodiment 2

[0089] From 5-(2-methoxyphenyl)-2-(pyrimidin-2-yl)pyrimidine-4,6-(1H,5H)-dione (compound 1) 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (compound 2)

[0090] 343.70 g of phosphorus oxychloride was added, followed by 175.0 g of compound 1. The temperature of the reaction was raised to reflux. The reaction was stirred at reflux for 4.0 hours. The reaction was monitored by HPLC. The reaction was gradually cooled to 40-50°C. The reaction was quenched with 2.625 L of water at 5-10°C. The reaction was stirred at 5-10°C for 2.0 hours. Filter and wash the wet material three times with 175.0 ml of water. Unload wet material. Weight of wet compound 2: 255 g. The wet mass was vacuum dried at 55-60°C for 8.0 hours. Weight of dry compound 2: 182g (% yield: 93%; HPLC purity: >98%))

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Abstract

The present invention relates to processes for the preparation of an endothelial receptor antagonist. The present invention particularly relates to synthesis of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] benzene sulfonamide (bosentan).

Description

field of invention [0001] The present invention relates to methods for preparing endothelin receptor antagonists. More specifically, the present invention relates to 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)- Synthesis of 4-pyrimidinyl]benzenesulfonamide (bosentan). Background of the invention [0002] Bosentan represented by structural formula I is traded under the trade name Tracleer Marketed and labeled for the treatment of pulmonary arterial hypertension (WHO group I) in patients with WHO stage III / IV symptoms to improve exercise capacity and reduce the rate of clinical deterioration. [0003] [0004] Formula I [0005] Bosentan was first disclosed in US 5,292,740. The synthetic method for the preparation of bosentan disclosed in this patent describes the conversion of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine to 4-tert-butyl The conversion of yl-N-[6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide involve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/513A61P9/12
CPCC07D403/04C07D239/52A61P9/12
Inventor S·乔希R·坎D·本德里D·萨伦克S·古德卡尔
Owner SANDOZ LTD
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