Method for preparing macitentan

A technology of macitentan and compounds, applied in the field of chemical drug synthesis, can solve problems such as long reaction time and unsuitable purification methods for industrial production

Inactive Publication Date: 2015-03-25
NANJING CORE TECH CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0010] In the prior art, there are many documents on the synthesis research of macitentan, but the reaction time is long and the purification method is not suitable for industrial production. Therefore, a kind of macitentan with shorter reaction time and higher purity can be directly obtained through research and development. The preparation method of citentan is very necessary

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  • Method for preparing macitentan

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Embodiment 1

[0030] Example 1: Preparation of macitentan

[0031] (1) N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N ， -Synthesis of Propyl Sulfonamide (Formula (Ⅳ))

[0032] 16.8g of N-propylsulfonamide and 150mL of anhydrous toluene were added to a 1L three-necked flask, and then 13g of sodium hydride was added in batches, stirred for 1h, and then slowly added 30g of 5-(4-bromophenyl)-4,6-dichloro Pyrimidine, stirred at room temperature and reacted for 6-8 hours. After the reaction was monitored by TLC, the above reaction solution was poured into 1.2L of ice water, stirred while adding, and the insoluble solid was filtered out by suction. The filtrate was 120ml, 6mol / L dilute hydrochloric acid Adjust the pH to 3~4, a large amount of solids precipitate out, and filter with suction to obtain N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N ， -Propylsulfonamide. 26.9g, yield: 67.3%.

[0033] (2) N-5-(4-bromophenyl)-6-(2-2-hydroxyethoxy-)4-pyrimidinyl-N ， -Propyl Sulfonamide (Formula (VI) Synthesis

[0...

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Abstract

The invention discloses a method for preparing macitentan. The method comprises the following steps: (1) carrying out a substitution reaction between a compound N-propanesulfonamide of a formula (II) and a compound 5-(4-bromophenyl)-4,6-dichloropyrimidine of a formula (III) so as to convert into a compound of a formula (IV); (2) carrying out a substitution reaction between the compound of the formula (IV) and a compound of a formula (V) in the presence of a strong base, thereby obtaining a compound of a formula (VI); and (3) carrying out a substitution reaction between the compound of the formula (VI) and a compound of a formula (VII) in the presence of a strong base, thereby obtaining the compound (macitentan) of the formula (I). The process conditions of the method for preparing macitentan are mild, the reaction time is greatly shortened, the after-treatment is simple, the purity is high, the reaction cost is low, and the industrial production is easily realized.

Description

Technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and relates to N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl ]-N-Propylsulfonamide (macitentan) preparation method. Background technique [0002] Macitentan (macitentan), chemical name is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidine 基]-N-propylsulfonamide, the structural formula is as follows: [0003] [0004] Macitentan was approved by the FDA on October 18, 2013 for the treatment of pulmonary arterial hypertension (PAH). Macitentan is an antagonist of dual endothelin receptor A and B (ETA and ATB). The trade name is Opsumit, developed by Actelion Pharm. [0005] There are many synthetic methods for macitentan, and the methods reported in the literature are summarized as follows: [0006] (1) The method of synthesizing macitentan reported by Martin H. Bolli et al. is as follows: [0007] [0008] The method uses 5-(4-bromopheny...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 王雪根何凌云郭莉芹李晓静刘静
Owner NANJING CORE TECH CO LTD
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