METHOD OF PRODUCING AVATROMBOPAG Russian patent published in 2019 - IPC C07D417/14 A61K31/426 

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for preparing avatrombopag or maleate thereof. Compound corresponds to the following structural formula (I), has the properties of a thrombopoietin receptor agonist (aTPO-r) and can be used for treating thrombocytopenia.

(1)

Method comprises adding dropwise Br₂ to solution of 2-acetyl-4-chlorothiophene (1) in diethyl ether, extraction is carried out with ethyl ether of acetic acid (EtOAc), the residue is dissolved in ethyl alcohol, thiourea is added and subjected to boiling. Resulting residue is dissolved in a mixture of EtOAc/hexane, having ratio by volume of 1:1, dropped after cooling to room temperature, filtered precipitate of 4-(4-chlorothiophen-2-yl)thiazole-2-amine (2) is washed with a mixture of EtOAc/hexane and dried in a vacuum at room temperature, is dissolved in dioxane and N-bromosuccinimide is added to obtain 4-(4-chlorothiophen-2-yl)thiazole-4-bromo-2-amine (3), as well as a characteristic impurity of 5-bromo-4-(5-bromo-4-chlorothiophen-2-yl)thiazole-2-amine, which then reacts similarly to (3), dissolving the product in acetonitrile, adding 1-cyclohexylpiperazine and triethylamine, carrying out reaction during boiling. Precipitate of 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazole-2-amine (4) precipitated during cooling is filtered, washed with water, hexane and diethyl ether and dried, the obtained product is added to pyridine solution of 5-chloro-6-(4-ethoxycarbonyl)piperidin-1-yl)nicotinic acid (7), which is obtained by adding to the solution of ethyl-piperidine-4-carboxylate (5) in dimethylsulphoxide 5,6-dichloronicotinic acid (6) and triethylamine, followed by heating to temperature of 150 °C, crystallization, washing with water, hexane, drying at room temperature and dissolving (7) in pyridine. Then cooled solution of mixture (4) and (7) is added with phosphorus oxychloride (POCl₃) so that mixture temperature does not exceed 10 °C is heated to room temperature, crystallization reaction is carried out, obtained crystalline precipitate of ethyl ether of avatrombopag (8) is washed with water and hexane, the powder is dried, dissolved in a mixture of toluene and ethyl acetate, having ratio by volume of 10 to 1, purified by flash chromatography on silica gel, suspended in a mixture of distilled water and tetrahydrofuran, adding sodium hydroxide at room temperature, stirring, diluting with water, adding acetic acid to the obtained solution until pH=5–5.5, stirring at room temperature until crystallization ends and precipitation of avatrombopag (9). Obtained precipitate is filtered and washed with water, a mixture of tetrahydrofuran and water, then with water, hexane and ethyl acetate, and dried with subsequent treatment of the obtained product with maleic acid to obtain maleate of avatrombopag.

EFFECT: method enables to exclude heating during hydrolysis of ether, significantly reduce the characteristic impurity of 5-bromo-4-(5-bromo-4-chlorothiophen-2-yl)thiazole-2-amine to trace amounts and improve purification of the obtained intermediate compounds; yield of the obtained product is 94,5 %, purity is 98 % NMR.

1 cl, 3 ex