FIELD: chemistry.
SUBSTANCE: invention relates to a method of producing methyl{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, where the X-ray diffraction pattern of said compound in modification I shows maximums of peak of angle 2-theta at 5.9, 6.9, 22.7. According to the disclosed method, a hydrochloride of a compound of formula (I) is obtained by heating the compound of formula (IX) in tetrahydrofuran as a solvent, adding 1.0 to 1.2 eq. of methyl chloroformate, stirring for a reaction time of 1 to 10 hours and isolating the hydrochloride of the compound of formula (I). Di-DMSO solvate of the compound of formula (I) is then obtained by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, crystallising the di-DMSO solvate by cooling and adding ethyl acetate, separating the di-DMSO solvate in crystalline form and washing with a mixture of DMSO and ethyl acetate. Compound of formula (I) is then obtained in the crystalline form of modification I, where 1.1) di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol is added at the ratio of DMSO to ethanol from 2:1 to 6:1 wt./wt.; 1.2) the dissolved compound of formula (I) is then crystallized from the solution by adding water; 1.3) formed suspension is then cooled to temperature from 5 °C to 50 °C and 1.4) the formed crystals in step 1.2 are then agglomerated to obtain a product of the active compound by adding isopropyl acetate, where ratio of weight of isopropyl acetate and sum of weight of compound of formula (I) plus weight of ethanol ranges from 0.3 to 2.0. Invention also relates to a version of the method of producing a compound of formula (I) and a method of producing the hydrochloride of the compound of formula (I).
EFFECT: method enables to obtain the desired compound with high output, high degree of purity and improved physical characteristics.
9 cl, 2 dwg, 17 ex
Title |
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Author |
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PRODUCT OF ACTIVE COMPOUND OF METHYL{4,6-DIAMINO-2-[5-FLUORO-1-(2-FLUOROBENZYL)-1H-PYRAZOLO[3,4-B]PYRIDIN-3-YL]PYRIMIDIN-5-YL}CARBAMATE, HAVING IMPROVED PROPERTIES, PREPARATION AND COMPOSITION THEREOF |
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