CRYSTALLINE FORMS OF BTK INHIBITOR Russian patent published in 2024 - IPC C07D239/47 A61K31/505 A61P35/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a crystalline form of a compound, which is N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, characterized by a powder X-ray diffraction pattern containing characteristic peaks expressed in 2θ selected from the group consisting of the value °2θ making 7.8 ± 0.2, 9.2 ± 0.2, 12.0 ± 0.2, 13.6 ± 0.2, 15.6 ± 0.2, 16.0 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 22.1 ± 0.2, 23.4 ± 0.2, 23.9 ± 0.2, 24.8 ± 0.2, 25.2 ± 0.2, 25.5 ± 0.2, 27.2 ± 0.2, and 29.6 ± 0.2, measured at temperature of approximately 25 °C, and x-ray wavelength, λ, component of 1.5405 Å, where one characteristic peak has value of 9.2 ± 0.2°2θ. Method comprises steps of (a) reaction of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide with acrylic acid anhydride in a non-chlorinated solvent, in the presence of a carbonate base at a temperature of approximately 40 °C to approximately 65 °C, where the non-chlorinated solvent is ethyl acetate; and (b) separating said crystalline form as a solid by distillation or evaporation of ethyl acetate to obtain a suspension which is then cooled to 0 °C and filtered to recover said crystalline form; and where the term "approximately" means a deviation ±5%.

EFFECT: stable, non-hygroscopic crystalline form of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

12 cl, 9 dwg, 13 tbl, 7 ex