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：
RU2019124406
公开号：
RU0002709493C1
申请日:
2019.08.01
申请国别(地区):
RU
年份:
2019
代理人:
摘要：
FIELD: pharmaceutics.SUBSTANCE: invention relates to a novel improved method of producing roxadustat of formula 11. Roxadustat is used in treating anemia and chronic renal insufficiency. Method comprises obtaining trifluoromethane sulphonate by reacting 2-hydroxy-5-fluoroacetophenone with trifluoromethylsulphonic anhydride in dichloromethane in the presence of pyridine, trifluoromethane sulphonate is added with 1,3-bis(diphenylphosphino) propane and a palladium (II) acetate catalyst and reacting in carbon monoxide medium under vacuum to form an intermediate product of formula 3, which is dissolved in methanol, sodium borohydride is added, obtained mixture of lactone of formula 4 and its open form 4''is converted into lactone (5)-3-methyl-5-phenoxy isobenzofuran-1(3H)-one by reaction with dry potash phenol medium, obtained lactone (5), toluene, trimethyl borate and thionyl chloride are heated, concentrated, extracted with an organic solvent and dried to obtain 2-(1-chloroethyl)-4-phenoxybenzoic acid methyl ester (6). It is reacted with addition of ethyl ether of p-toluenesulphonyl glycine, sodium iodide, potassium carbonate and N,N-dimethylformamide to form 2-(1-(N-methoxycarbonylmethyl-(toluene-4-sulphonyl)-amino)ethyl)-methyl ester of 4-phenoxybenzoic acid (7), to which methanol and sodium methoxide are added to form a compound of formula 8, then from compound of formula 8 by reaction in mixture of methyl alcohol and water with addition of sodium hydroxide and stirring at 80–90 °C for 10 hours obtaining an acid of formula 9, acid is amidated to obtain amide of formula 10by adding to solution of acid of formula 9 in acetonitrile of diisopropylethylamine, hydrochloride of ethyl glycine ester and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and acidified with acetic acid to pH=4.0–4.5, or a mixture of the obtained amide of formula 10, ethyl alcohol and water is reacted while sodium hydroxide is added while stirring at room temperatu
