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Method for refining high-purity macitentan

A refining method and technology of macitentan, applied in the field of refining endothelin receptor antagonist macitentan, can solve the problems of difficult crystal removal, poor solubility, increase of impurity L and impurity M, etc., and achieve product purity and High yield, low production cost, and easy operation

Active Publication Date: 2016-04-06
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the heating and dissolving process of macitentan crystals, impurity J, impurity N, and impurity K will increase, and impurity J has poor solubility in common organic solvents, making it difficult to remove crystals
[0011] The literature (MartinH.Bollietall.JournalofMedicinalChemistry.Pages7849-7861.) is refined with methanol. Experiments have proved that this method can effectively remove the impurities in the macitentan process, but it cannot effectively remove the degraded impurity J, and it will cause the increase of impurities L and M. Impurity J, impurity L and impurity M will further increase after methanol recrystallization, and the product purity is limited
[0012] Patent CN201410778483.8 adopts methanol beating and refining at room temperature. The experiment proves that this method will not cause the increase of impurity L and impurity M, but it cannot remove impurity J, and the impurity removal is not thorough, so it is not suitable for industrial production
[0013] The existing refining method cannot effectively remove the degraded impurity J, and the increase of the oxidized impurity L and impurity M after heating and refining is inevitable, and the product purity cannot be effectively improved

Method used

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  • Method for refining high-purity macitentan
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  • Method for refining high-purity macitentan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Heat 100ml of ethyl acetate at 76-80°C to reflux and boil for 30min. Under the condition of avoiding light, add 20g of macitentan crude product, stir and dissolve at 76-80°C, add 0.2g of activated carbon, stir for decolorization for 10min, press filter while hot, The filtrate was protected from light and cooled to 45-50°C, stirred and crystallized for 1.5h, then slowly cooled to 25-30°C, stirred and crystallized for 1h, filtered, and dried under reduced pressure at 35-45°C for 8h to obtain 18.4g of pure macitentan. Yield 92.0%, purity 99.94%.

Embodiment 2

[0055] Mix 75ml of methanol and 375ml of ethyl acetate, heat and reflux at 68-75°C for 1h, put in 20g of crude macitentan under the condition of avoiding light, stir and dissolve at 60-70°C, add 0.2g of activated carbon, stir for 15min to decolorize, Hot press filtration, the filtrate was protected from light and cooled to 50-55°C, stirred and crystallized for 2 hours, then slowly cooled to 20-25°C, stirred and crystallized for 1.5 hours, filtered, dried under reduced pressure at 35-45°C for 6 hours, and pure macitentan was obtained. Product 17.8g, yield 89.0%, purity 99.97%.

Embodiment 3

[0057] Mix 200ml of ethyl acetate and 300ml of n-hexane, heat and reflux at 70-80°C for 1 hour, put in 20g of the crude product of macitentan under the condition of avoiding light, stir and dissolve at 70-80°C, add 0.2g of activated carbon, stir for 5min to decolorize, Press filter while it is hot, cool the filtrate to 45-50°C in the dark, stir and crystallize for 1.5h, then slowly cool down to 20-25°C, stir and crystallize for 1h, filter, and dry under reduced pressure at 35-45°C for 4h to obtain macitentan Pure product 17.3g, yield 86.5%, purity 99.98%.

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Abstract

The invention discloses a method for refining high-purity macitentan. The method comprises the steps of heating and dissolving crude macitentan by using a newly-boiled solvent in the absence of light, adding active carbon to perform decoloration for 5-15 min, performing filter pressing while the solution is hot, cooling filtrate to 45-55 DEG C in the absence of light and performing crystallization for 1-2 h with stirring, performing cooling to 20-30 DEG C to perform crystallization for 1-2 with stirring, and performing filtration and drying to obtain pure macitentan. The method has the advantages that the method is simple and convenient to operate and high in yield and the product is pure, the yield is 85% or above, and the purity of pure macitentan is 99.9% or above (according to high performance liquid chromatography (HPLC) detection).

Description

1. Technical field [0001] The invention relates to a purification method of chemical medicine, in particular to a purification method of macitentan, an endothelin receptor antagonist. 2. Background technology [0002] Macitentan (Macitentan) is a bidirectional endothelin receptor antagonist developed by Actelion Pharmaceuticals Inc. in Switzerland. It was approved by the U.S. FDA on October 18, 2013. Its trade name is Opsumit, which is used for the treatment of pulmonary arterial hypertension (PAH) to delay the progression of the disease. Its chemical name is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propane Sulfonamide, the chemical structural formula is as follows formula (I): [0003] [0004] The impurities contained in macitentan are closely related to its structure and synthesis process. Its molecular structure can be divided into four key fragments as follows: 5-(4-bromophenyl)-4,6-disubstituted pyrimidine (fragment 1), N-pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 吴标凌林唐胜国卫强
Owner HEFEI JIUNUO MEDICAL TECH
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