Balabanyan Vadim Yurevich (RU),Балабаньян Вадим Юрьевич (RU),Fazylov Marat Feliksovich (RU),Фазылов Марат Феликсович (RU),Nesteruk Vladimir Viktorovich (RU),Нестерук Владимир Викторович (RU)
申请号：
RU2019124410
公开号：
RU0002709496C1
申请日:
2019.08.01
申请国别(地区):
RU
年份:
2019
代理人:
摘要：
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, cr
