Method for refining high-purity macitentan

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...

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

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