CRYSTALLINE Μ-MODIFICATION OF 1-[(3R)-3-[4-AMINO-3-(4-PHENOXY-PHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]-1-PIPERIDYL]-2-PROPENYL-1-ONE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON Russian patent published in 2020 - IPC C07D487/04 A61K31/519 A61P35/00 

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a novel crystalline modification of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propenyl-1-one (Ibrutinib - international non-proprietary name). Crystalline Ibrutinib μ-modification is characterized by the following set of interplanar distances (d, Å) and corresponding intensities (I_rel., %): 15.477 Å - 42.64 %; 11.171 Å - 19.92 %; 9.896 Å - 17.53 %; 8.207 Å - 35.06 %; 7.137 Å - 28.61 %; 6.716 Å - 27.49 %; 6.433 Å - 39.13 %; 6.200 Å - 36.19 %; 5.849 Å - 35.62 %; 5.641 Å - 43.20 %; 5.516 Å - 43.90 %; 5.268 Å - 46.14 %; 5.053 Å - 49.65%; 4.845 Å - 59.61%; 4.667 Å - 70.13%; 4.581 Å - 63.67 %; 4.454 Å - 69.57 %; 4.316 Å - 59.61 %; 4.267 Å - 57.22 %; 4.152 Å - 100.00 %; 4.084 Å - 73.07 %; 3.955 Å - 53.16 %; 3.920 Å - 50.91 %; 3.863 Å - 47.41 %; 3.776 Å - 52.59 %; 3.732 Å - 39.69 %; 3.627 Å - 35.62 %; 3.578 Å - 39.13 %; 3.536 Å - 34.50 %; 3.476 Å - 35.62 %; 3.350 Å - 43.20 %; 3.259 Å - 31.00 %; 3.137 Å - 29.87 %; 3.082 Å - 32.12 %; 2.983 Å - 25.67 %; 2.937 Å - 25.11 %; 2.825 Å - 22.16 %; 2.768 Å - 19.35 %; 2.708 Å - 20.48 %; 2.610 Å - 16.97 %; 2.571 Å - 15.85 %; 2.482 Å - 16.41 %; 2.387 Å - 17.53 %; 2.379 Å - 16.97 %; 2.295 Å - 17.53 %; 2.240 Å - 14.59 %; 2.162 Å - 14.59 %. Method of producing crystalline μ-modification of Ibrutinib is performed by mixing the solution of Ibrutinib in an organic solvent at 25–80 °C with water in ratio of 1:2–1:4. Then it is frozen at cooling rate not lower than 60 deg/min, sublimated drying and additionally annealed at (90–110) °C during (0.5–5.0) hours. Invention also relates to a method of producing crystalline μ-modification of Ibrutinib, carried out by reacting (3R)-4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine with acryloyl chloride, wherein at the product crystallisation step a small amount of seed is introduced μmodification of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propenyl-1-one.

EFFECT: crystalline μ-modification of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-2-propenyl-1-one is intended for preparing a pharmaceutical composition as a covalent selective Bruton tyrosine kinase inhibitor for treating mantle cell lymphoma and chronic lymphocytic leukaemia.

5 cl, 5 ex, 4 tbl, 4 dwg