METHOD OF PRODUCING ROXADUSTAT Russian patent published in 2019 - IPC C07D217/26 A61P7/06 A61P9/12 

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 10

by 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 temperature for 10–15 hours. After the reaction, the mixture is filtered, diluted with water and acidified with acetic acid till pH=4.0–4.5, stirred, and then the precipitate is filtered, washed with water, hexane and diethyl ether, followed by drying the obtained powdered roxadustat of formula 11

.

EFFECT: method enables to obtain an end product with output of up to 86 % and high degree of purity (up to 98 %) without further purification.

1 cl, 2 dwg, 3 ex