PRODRUG OF POLYMERASE NS5B HCV INHIBITOR, METHOD FOR ITS PREPARATION AND APPLICATION Russian patent published in 2018 - IPC C07H19/10 C07F9/22 A61K31/7072 A61K31/664 A61K31/675 A61P31/20 

FIELD: medicine; pharmaceuticals.

SUBSTANCE: present invention relates to a novel prodrug which is cyclobutyl (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-ylmethoxy]phenoxy-phosphorylamino}-propanoate of general formula 1, its stereoisomer, or polycrystalline form. Stereoisomers of this compound are cyclobutyl (S)-2-{(S)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.1 or cyclobutyl (S)-2-{(R)-[(2R,3R,4R,5R)-5-(3,4-dihydro-2,4-dioxo-2H-pyrimidin-1-yl)-3-hydroxy-4-methyl-4-fluoro-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propanoate of formula 1.2. Polycrystalline form of these compounds is a mixture of rhombic and monoclinic forms. Crystalline form is a rhombic form. Method for preparation of the prodrug of formulas 1, 1.1 and 1.2 is the reaction of cyclobutyl (S)-2-(pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2 or cyclobutyl (S)-2-((S)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.1 or cyclobutyl (S)-2-((R)-pentafluorophenyloxy-phenoxy-phosphorylamino)-propionate of formula 2.2 with tert-butyl(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-2-(hydroxymethyl)-4-methyl-4-fluoro-tetrahydrofuran-3-yl carbonate of formula 7 in the presence of an alkyl magnesium halide, followed by deprotection.

EFFECT: prodrug has the properties of a polymerase NS5B HCV inhibitor and can be used in treatment of hepatitis C.

10 cl, 10 ex, 3 tbl