CRYSTALLINE FORM OF MONOETHANOLAMINE 3'-[(2Z)-2-[1-(3,4-DIMETHYLPHENYL)-1,5-DIHYDRO-3-METHYL-5-OXO-4H-PYRAZOLE-4-YLIDENE]HYDRAZINO]-2'-HYDROXY-[1,1'-BIPHENYL]-3-CARBOXYLIC ACID Russian patent published in 2022 - IPC C07D231/46 A61K31/4152 A61P7/00 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a method for producing an improved thrombopoietin (TPO) mimetic applied in medicine, constituting monoethanolamine 3′-[(2Z)-2-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid in crystalline form. Method for producing the crystalline form B of monoethanolamine 3′-[(2Z)-2-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid is implemented by pouring a solution of hydrochloric acid into a reactor and adding 3′-amino,2′-hydroxy-(1,1′-biphenyl)-3-carboxylic acid thereto. The reaction mass is then heated to 55°C and held until full dissolution, followed by cooling the resulting solution to 0°C and dosing a solution of sodium nitrite at a temperature of 5°C or lower; after 1 hour, adding 2-(3,4-dimethylphenyl)-5-methyl-1,2-dihydro-3H-pyrazole-3-one to the resulting solution. Upon the end of dosing, ethanol and sodium hydrocarbonate are added to the reaction mass, the formed deposit is filtered, and the mother liquor is treated with monoethanolamine at a temperature of 60°C; after 1 hour, the reaction mass of 3′-[(2Z)-2-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid is cooled, filtered, and taken off the filter. The resulting deposit is dissolved in dimethylformamide and added to ethyl acetate, stirred for 6 hours, and filtered. The deposit on the filter is washed with water multiple times and dried, resulting in 3′-[(2Z)-2-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid in the form of a crystalline form B characterised by the powder X-ray diffraction pattern thereof displaying characteristic peaks at 6.5; 10.9; 11.1; 11.4; 14.2; 14.6; 15.4; 16.7; 21.7; 24.5; 25.8; 26.1; 26.3; 29.1 +(-)0.2° 2θ.

EFFECT: production of a polymorphic form of monoethanolamine 3′-[(2Z)-2-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid exhibiting increased stability and lower toxicity.

1 cl, 2 dwg, 9 tbl, 7 ex