METHODS OF PRODUCING INFLUENZA VIRUS REPLICATION INHIBITORS Russian patent published in 2019 - IPC C07D471/04 

FIELD: chemistry.

SUBSTANCE: invention relates to versions of an improved method of producing a compound of formula (1) or a pharmaceutically acceptable salt thereof. Compound of formula (1) is used as an inhibitor of influenza virus replication. Method of obtaining compound (1) having structural formula (1) includes a) reacting compound (X) or a pharmaceutically acceptable salt thereof with compound (Y) (X), (Y), (Z) in the presence of a palladium catalyst and a base to form compound (Z) or a pharmaceutically acceptable salt thereof; and (b) removing the protective group Ts from compound (Z) or a pharmaceutically acceptable salt thereof to form compound (1) or a pharmaceutically acceptable salt thereof. Each of X¹ and X² independently represents -F or -Cl; Ts is tosyl; the palladium catalyst comprises a palladium-XPhos complex, in which XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; the base is a phosphate base or carbonate base, and the reaction in step (a) is carried out in a solvent system comprising water and an organic solvent selected from 2-methyl-tetrahydrofuran or tetrahydrofuran (THF), or any combination thereof. Palladium-XPhos complex can be obtained in situ by mixing Pd(OAc)₂ and Xphos. Base is a phosphate base or a carbonate base selected from Na₂CO₃, K₂CO₃, K₃PO₄ or Na₃PO₄. At step (b), compound (Z) or a pharmaceutically acceptable salt thereof is treated with an inorganic hydroxide, including LiOH, NaOH, KOH, or any combination thereof in a solvent system that comprises THF. Or, the method of obtaining compound (I) additionally includes step (g) of reacting compound (A) (A) with quinine and ethyl alcohol at a temperature from -12 °C to -16 °C to form an adduct of quinine and compound (C-1), h) breaking down the adduct of quinine and compound (C-1) by treating the adduct with HCl at a temperature below 25 °C to form compound (C-1) or a pharmaceutically acceptable salt thereof; (i) epimerization of compound (C-1) or pharmaceutically acceptable salt thereof to form compound (C) or a pharmaceutically acceptable salt thereof, where the epimerization involves treating compound (C-1) with alkali metal C_1-6alkoxide at a temperature of -15 °C to -22 °C; (e) reacting compound (C) or pharmaceutically acceptable salt thereof with diphenylphosphoryl azide and benzyl alcohol to form compound (D), where Cbz is carboxybenzyl; (f) reacting compound (D) or a pharmaceutically acceptable salt thereof with H₂ in the presence of a Pd catalyst on carbon (Pd(0)/C) to form the compound (F) (C-1), (C), (D), (F), (G), (H) or a pharmaceutically acceptable salt thereof; (c) reacting compound (F) or a pharmaceutically acceptable salt thereof with compound (G) to form compound (H) or a pharmaceutically acceptable salt thereof; (d) hydrolysing compound (H) or a pharmaceutically acceptable salt thereof to form compound (X) or a pharmaceutically acceptable salt thereof. Further, method comprises carrying out steps (a) to (b) to obtain compound (1) as described above. Invention also includes a method for producing compound (1) from compound (K), as well as a method for producing compound (C) and a method for producing compound (2) corresponding to structural formula (1), where each X¹ and X² is F.

EFFECT: method allows to obtain compound (1) with a degree of conversion of 99,9 % in 1,25 hours, which significantly speeds up previously known methods when carrying out the method with other catalysts.

57 cl, 29 tbl, 13 ex