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Method for preparing macitentan

A technology of macitentan and compounds, applied in the field of preparation of macitentan, can solve problems such as uneconomical and increased production costs, and achieve the effects of low production costs, cheap raw materials, and easy availability of raw materials

Inactive Publication Date: 2016-01-27
重庆瑞泊莱医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] As can be seen from the above synthetic route, it is not economical to connect n-propylaminosulfonamide first, and then to cheap ethylene glycol, which will lead to an increase in production cost and cannot ideally meet the requirements of industrialized preparation of macitentan

Method used

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  • Method for preparing macitentan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] a) Preparation of compound 3: 2-[(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)oxy]ethanol

[0039] Add 10mL of N,N-dimethylformamide and 1.0g of sodium hydrogen (60%) into a 50mL three-necked flask, cool to 0°C with icy brine under stirring, add 0.62g of ethylene glycol (compound 2) dropwise, and stir for 10min after the addition ; Add dropwise a solution of 15mL N,N-dimethylformamide and 3g 5-(4-bromophenyl)-4,6-dichloropyrimidine (compound 1) at 0°C under temperature control, and stir for 5h ; Slowly add 30mL saturated ammonium chloride solution, after the addition, stir for 10min; extract with 3×30mL ethyl acetate, combine the organic layer, wash with 3×30mL water; dry the organic layer with 5g anhydrous magnesium sulfate; , the residue was passed through the column with ethyl acetate and petroleum ether to obtain 2.5 g of compound 3: 2-[(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)oxy]ethanol;

[0040] [M+H] + = 329;

[0041] 1 HNMR (CDCl 3 ): δ3.80~3.84(...

Embodiment 2

[0051]

[0052] A) Preparation of compound 8: 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol

[0053] Add 50mL tetrahydrofuran, 2.1g 5-bromo-2-chloropyrimidine (compound 6), 4.3g benzotriazole-1-tris(trimethylamino)-trifluorophosphate and 3.3g cesium carbonate into a 100mL three-necked flask, and stir for 1h ; Add 11g ethylene glycol (compound 2) and 3.3g cesium carbonate, stir the reaction at room temperature for 10h; slowly add 100mL water, extract with 3×50mL ethyl acetate, combine the organic layers, wash with 3×30mL water; 5g anhydrous Dry the organic layer with magnesium sulfate; rotary evaporate in a water bath at 40°C, and pass the residue through a column with ethyl acetate and petroleum ether to obtain 1.4 g of oil compound 8: 2-[(5-bromo-2-pyrimidinyl)oxy] ethanol;

[0054] [M+H] + = 219;

[0055] 1 HNMR (CDCl 3 ): δ3.90~3.96 (2H, m), δ4.43~4.47 (2H, m), δ8.52 (2H, s).

[0056] B) Preparation of compound 10: 5-(4-bromophenyl)-4-[2-[(5-bromo-2-pyrimidinyl)oxy]ethanol...

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Abstract

The invention discloses a method for preparing macitentan. The method comprises a following synthesis route. As a result of experiments, the method provided by the invention has the advantages of simple operation, mild reaction conditions, low requirement on equipment, inexpensive and easy-to-obtain raw materials, and low production cost. The method can be easily applied in large-scale productions. The method meets the requirements of macitentan industrialized production, and has industrial application value.

Description

technical field [0001] The invention relates to a method for preparing macitentan, which belongs to the technical field of organic chemistry. Background technique [0002] Macitentan is an oral ETA and ETB dual antagonist researched and developed by Swiss Actelion Company. It is an endothelin receptor antagonist after Bosentan and Ambrisentan. Approved for the treatment of adult patients with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating disease that can lead to death or require lung transplantation. [0003] Macitentan, trade name Opsumit, English name macitentan, chemical name N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] Ethoxy]-4-pyrimidinyl]-N'-propylsulfonamide. [0004] The original research patent WO2002053557 reported the synthesis method of macitentan: [0005] 1) Prepare macitentan with 4-bromophenylacetic acid methyl ester as starting material, and its synthetic route is as follows: [0006] [0007] Wherein, the ...

Claims

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Application Information

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IPC IPC(8): C07D239/47
Inventor 李伟高河勇陈琳
Owner 重庆瑞泊莱医药科技有限公司
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