RU2711106C2 - 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 - Google Patents

Abstract

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, %): 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

Description

The invention relates to organic chemistry and relates to a new 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 - the international nonproprietary name), the μ modification we called, the method for its preparation and its pharmaceutical composition, which can be used in the pharmaceutical industry and medicine as a covalent selective tyrosine kinase inhibitor Bruton for the treatment of mantle cell lymphoma and chronic lymphocyte th leukemia.

Substituted cyclic compounds and their pharmaceutically acceptable salts are known as a covalent selective Bruton tyrosine kinase inhibitor, methods for their preparation and pharmaceutical compositions containing them for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. (WO 2008/039218 A2 of 04/03/2008; WO 2013/138210 A1 of 09/19/2013; CN 103121999 A of 05/29/2013; CN 104447761 A of 03/25/2015; WO 2015/026934 A1 dated February 26, 2015; US 2015/0105409 A1 dated April 16, 2015; WO 2014/139970 A1 dated September 18, 2014; CN 104557946 A dated April 29, 2015; CN 103626774 A dated March 12, 2014. ; CN 103534258 A dated 01/22/2014; WO 2016/066726 A2 dated 05/06/2016; CN 106008526 A dated 12/10/2016; CN 101674834 A dated 03/17/2010, etc.).

However, in these patents, the synthesized substances are not characterized for their belonging to a particular polymorphic modification and the parameters of the obtained powders are not determined. These properties ultimately determine the biological activity of the resulting substances.

Crystalline and amorphous pharmaceutically acceptable salts of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] are known -2-propenyl-1-one, their solvates and hydrates, including their various polymorphic forms, as well as solvates of ibrutinib with various solvents and mixtures thereof. (WO 2016/127960 A1 of 08/18/2016; WO 2016/139588 A1 of 09/09/2016; WO 2013/184572 A1 of 12/12/2013; US 2012/0077832 A1 of 03/29/2012; EAP 2013/00246 A1 dated January 30, 2014; CN 103923084 A dated July 16, 2014; WO 2016/025720 A1 dated February 18, 2016; WO 2014/022390 A1 dated February 16, 2014; WO 2015/145415 A1 dated October 1, 2015; WO 2016/079216 A1 dated May 26, 2016; WO 2016/207172 A1 dated December 29, 2016; WO 2016/160598 A1 dated October 6, 2016; US 2012/0077835 A1 dated March 29, 2016 .2012; US 9422295 B2 dated August 23, 2016; CN 106008529 A dated October 12, 2016; WO 2017/085628 A1 dated May 26, 2017; WO 2012/022444 A1 dated February 16, 2012, etc. .).

However, all these forms differ from the claimed new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl] -1-piperidyl] -2-propenyl-1-one with the chemical composition — the presence of acid anions in the chemical formula or the presence of solvate molecules.

Closest to the claimed new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- il] -1-piperidyl] -2-propenyl-1-one are crystalline polymorphic modifications of ibrutinib: Form A, Form B, Form C, Form D1, Form B, Form F, Form G, Form K, Form S1, Form S2 , form S3, form S4, Form A (in another source of the same authors it is form I), form I, form II, form III, form VI, form α, form β, form γ, form δ, form ε, form ζ and amorphous form (WO 2013/184572 A1 dated 12.12.2013; WO 2016/139588 A1 dated 09/09/2016; CN 105646484 A dated 8 06.06.2016; CN 105646498 A dated 06/08/2016; CN 105646499 A dated 06/08/2016; WO 2016/025720 A1 dated 02/18/2016; WO 2017/029586 A1 dated 02/23/2017; WO 2015/081180 A1 dated June 4, 2015; CN 104327085 A dated June 8, 2016; CN 105294696 A dated February 3, 2016; CN 106117214 A dated November 16, 2016; WO 2015/145415 A1 dated June 4, 2015 g .; EP 3243824 A1 dated November 15, 2017, etc.).

) и их интенсивностью (I, имп./мин; I_отн., = I_i/I_max×100, %) или непосредственно рентгенограммами (получение дифрактограмм авторы вышеприведенных патентов проводили на Cu Kα - излучении), термоаналитическими исследованиями (температурами тепловых эффектов) и другими.Known crystalline modifications of ibrutinib are characterized by physicochemical methods of analysis such as: nuclear magnetic resonance (NMR) - a set of chemical shifts (ppm), X-ray phase analysis (XRD) - sets of angles (2θ, degrees), interplanar distances ( d

) and their intensity (I, imp. / min; I _rel. , = I _i / I _max × 100,%) or directly by X-ray diffraction patterns (the diffraction patterns were obtained by the authors of the above patents using Cu Kα radiation), thermoanalytical studies (thermal effects temperatures) ) and others.

The similarity of the claimed new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, with known crystalline modifications of ibrutinib, is the identity of their chemical compositions.

), и их интенсивностью (I_отн., = I_i/I_max×100, %).The difference between the claimed new, previously unknown, crystalline and 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, from the known crystalline modifications of ibrutinib lies in the difference in their X-ray diffraction patterns (XRD): a certain set of angles 2θ (degrees) - interplanar distances (d,

), and their intensity (I _rel. , = I _i / I _max × 100,%).

Known crystalline modifications of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl -1-he are white or almost white powders, readily soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.

Modifications of ibrutinib discussed above are obtained from various starting components or one of the other in solutions, varying the type of solvent, the conditions for the preparation of solutions, as well as the conditions for isolation from organic solvents or their mixtures by various methods, such as crystallization from solutions, followed by filtration, washing, drying in air, by vacuum drying, spray drying or freeze-drying (WO 2013/184572 A1 dated 12.12.2013; WO 2016/139588 A1 dated 09/09/2016; CN 105646484 A dated 06/08/2016; CN 105646498 A dated 06/08/2016; CN 105646499 A dated 8/06/2016; WO 2016/025720 A1 from 02/18/2016; WO 2017/029586 A1 from 02/23/2017; WO 2015/081180 A1 from 4/06/2015; CN 104327085 A from 8/08/2016; CN 105294696 A from 02/03/2016; CN 106117214 A dated 11/16/2016; WO 2015/145415 A1 dated 06/04/2015; EP 3243824 A1 dated 11/15/2017; WO 2017/137446 A1 dated 08/17/2017; WO 2016/088074 A1 of June 9, 2016; WO 2016/170545 A1 of 10/27/2016; WO 2017/174044 A1 of 12/10/2017; WO 2016/207172 A1 of December 29, 2016, etc.).

The closest in technical essence is a method for producing an amorphous modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1 -piperidyl] -2-propenyl-1-one, which consists in the fact that ibrutinib is dissolved in an organic solvent at temperatures of 40 ° C-50 ° C, using ultrasound to accelerate dissolution, frozen at -30 ° C on a plate of a sublimation unit, lyophilized (subjected to freeze-drying) at temperatures on the stove of -30 ° C ... + 50 ° C and pressure from 0.150 to 0.020 mbar for 48 hours. The authors did not indicate the freezing rate of the ibrutinib solution in the patent materials (WO 2016/079216 A1 of 05/26/2016).

The difference in the method of obtaining the claimed new, previously unknown, crystalline μ - modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- il] -1-piperidyl] -2-propenyl-1-one from the methods for producing known crystalline and amorphous forms of ibrutinib is that a solution of ibrutinib in an organic solvent at 25-80 ° C is mixed with water in a ratio of 1: 2- 1: 4, frozen at a cooling rate of not lower than 60 deg / min, freeze-dried and further annealed at temperatures (90-110) ° C for (0.5-5.0) hours.

The difference between the claimed pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia based on 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4 -d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one from the known composition (State Register of Medicinal Products of Russia - Instructions for the use of a medicinal product for medical use of Imbruvik® / Imbruvica®) is that as the active substance use therapist a tactically effective amount of a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl ] -1-piperidyl] -2-propenyl-1-one (ibrutinib).

The aim of the invention is to obtain a new, previously unknown, crystalline μ - modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- il] -1-piperidyl] -2-propenyl-1-one, development of a method for its preparation and its use in the pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia.

) и соответствующих им интенсивностей (I_отн., = I_i/I_max×100, %): 15,477

- 42,64%; 11,171

- 19,92%; 9,896

- 17,53%; 8,207

- 35,06%; 7,137

- 28,61%; 6,716

- 27,49%; 6,433

- 39,13%; 6,200

- 36,19%; 5,849

- 35,62%; 5,64l

- 43,20%; 5,516

- 43,90%; 5,268

- 46,14%; 5,053

- 49,65%; 4,845

- 59,61%; 4,667

- 70,13%; 4,58l

- 63,67%; 4,454

- 69,57%; 4,316

- 59,61%; 4,267

- 57,22%; 4,152

- 100,00%; 4,084

- 73,07%; 3,955

- 53,16%; 3,920

- 50,91%; 3,863

- 47,41%; 3,776

- 52,59%; 3,732

- 39,69%; 3,627

- 35,62%; 3,578

- 39,13%; 3,536

- 34,50%; 3,476

- 35,62%; 3,350

- 43,20%; 3,259

- 31,00%; 3,137

- 29,87%; 3,082

- 32,12%; 2,983

- 25,67%; 2,937

- 25,11%; 2,825

- 22,16%; 2,768

- 19,35%; 2,708

- 20,48%; 2,610

- 16,97%; 2,57l

- 15,85%; 2,482

- 16,41%; 2,387

- 17,53%; 2,379

- 16,97%; 2,295

- 17,53%; 2,240

- 14,59%; 2,162

- 14,59%.The goal is achieved by the present invention, namely, obtaining a new, previously unknown, 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, characterized by the following set of interplanar distances (d,

) and their corresponding intensities (I _rel. , = I _i / I _max × 100,%): 15,477

- 42.64%; 11,171

- 19.92%; 9,896

- 17.53%; 8,207

- 35.06%; 7,137

- 28.61%; 6,716

- 27.49%; 6,433

- 39.13%; 6,200

- 36.19%; 5,849

- 35.62%; 5.64l

- 43.20%; 5,516

- 43.90%; 5,268

- 46.14%; 5,053

- 49.65%; 4,845

- 59.61%; 4,667

- 70.13%; 4,58l

- 63.67%; 4,454

- 69.57%; 4,316

- 59.61%; 4,267

- 57.22%; 4,152

- 100.00%; 4,084

- 73.07%; 3,955

- 53.16%; 3,920

- 50.91%; 3,863

- 47.41%; 3,776

- 52.59%; 3,732

- 39.69%; 3,627

- 35.62%; 3,578

- 39.13%; 3,536

- 34.50%; 3,476

- 35.62%; 3,350

- 43.20%; 3,259

- 31.00%; 3,137

- 29.87%; 3,082

- 32.12%; 2,983

- 25.67%; 2,937

- 25.11%; 2,825

- 22.16%; 2,768

- 19.35%; 2,708

- 20.48%; 2,610

- 16.97%; 2,57l

- 15.85%; 2,482

- 16.41%; 2,387

- 17.53%; 2,379

- 16.97%; 2,295

- 17.53%; 2,240

- 14.59%; 2,162

- 14.59%.

This goal was also achieved by the development of a method for obtaining a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl] -1-piperidyl] -2-propenyl-1-one, which consists of a solution of ibrutinib in an organic solvent at 25-80 ° C, mixed with water in a ratio of 1: 2-1: 4, frozen at a cooling rate of not lower than 60 deg / min, freeze-drying and additionally annealing at temperatures (90-110) ° C for (0.5-5.0) hours.

In addition, the goal was achieved by using a new, previously unknown, crystalline μ - modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl] -1-piperidyl] -2-propenyl-1-one for the preparation of a pharmaceutical composition as a covalent selective Bruton tyrosine kinase inhibitor for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. The specified composition contains μ - modification of ibrutinib in a therapeutically effective amount and at least one pharmaceutically acceptable carrier, diluent, excipient or excipient.

No crystalline μ is known from the patent and scientific literature - modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl ] -1-piperidyl] -2-propenyl-1-one, the method for its preparation and its use in the pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia.

) и их интенсивностью (I_отн., %), предложены способ ее получения и применение ее для приготовления фармацевтической композиции в качестве ковалентного селективного ингибитора тирозинкиназы Брутона для лечения мантийноклеточной лимфомы и хронического лимфоцитарного лейкоза.We discovered a new, previously unknown, 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, characterized by a certain set of diffraction maxima (d,

) and their intensity (I _rel. ,%), a method for its preparation and its use for preparing a pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase inhibitor for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia are proposed.

The claimed new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one is a light powder of white or almost white color, readily soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water.

To clarify the essence of the claimed technical solution, the following tables and figures are attached to the description:

) и их интенсивности (I_отн., %) известных модификаций ибрутиниба по литературным источникам.Table 1. Angles 2θ, deg., Interplanar distances (d,

) and their intensity (I _rel. ,%) of the known modifications of ibrutinib according to literary sources.

) и их интенсивности (I_отн., %) известной кристаллической формы А ибрутиниба, которую использовали в качестве исходного вещества.Table 2. Angles 2θ, degrees, interplanar distances (d,

) and their intensity (I _rel. ,%) of the known crystalline form A of ibrutinib, which was used as the starting material.

) и их интенсивности (I_отн., %) новой, не известной ранее, кристаллической μ - модификации 1-[(3R)-3-[4-амино-3-(4-феноксифенил)-1H-пиразоло[3,4-d]пиримидин-1-ил]-1-пиперидил]-2-пропенил-1-он.Table 3. Angles 2θ, interplanar distances (d,

) and their intensity (I _rel. ,%) of a new, previously unknown, 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.

Table 4. Melting points and thermal effects of known modifications of ibrutinib from published sources.

Fig. 1. ¹ H NMR is the spectrum of the known crystalline form A of ibrutinib, which was used as the starting material.

Fig. 2. ¹ H NMR spectrum of a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl] -1-piperidyl] -2-propenyl-1-one.

Fig. 3. Diffraction pattern of the known crystalline form A of ibrutinib, which was used as the starting material.

Fig. 4. A typical diffraction pattern of a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- yl] -1-piperidyl] -2-propenyl-1-one.

A complex of physicochemical methods of analysis was carried out to identify the obtained substance.

Initially, the methods of nuclear magnetic resonance ( ¹ H NMR) and high-performance liquid chromatography (HPLC) established the identity of the chemical formulas of the well-known crystalline modification of ibrutinib form A, which was used as the starting material, and a new, previously unknown, crystalline μ-modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one .

The chemical shifts of the initial ibrutinib and the substance obtained from it were determined in its saturated solution in deuterated dimethyl sulfoxide (DMSO-D ₆ ) on a VXR-400 high-resolution NMR spectrometer (VARIAN, USA). The data obtained are shown in Fig. 1 and 2, respectively. Comparison of the results presented in Fig. 1 (the initial substance of ibrutinib), with the data shown in Fig. 2 [new, previously unknown crystalline μ - modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one] shows that NMR - ¹ H - the spectra of the initial and obtained from it substances are almost identical, ie the resulting substance is 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl -1-he.

Chromatographic mobility of the starting substance ibrutinib form A, which was used as the starting material and, obtained from it, a new, previously unknown, 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 was determined by HPLC on a Shimadzu LC-20A chromatograph with an SPD-M20A detector and 150 column length mm, diameter 4.6 mm, sorbent Grace Apollo C18 "Agilent" (USA) with detection at a wavelength of 260.8 nm. As the mobile phase B, a 0.05% solution of trifluoroacetic acid in acetonitrile was used, and the mobile phase A was used as a 0.05% solution of trifluoroacetic acid in water, the column temperature was 40 ° C and the flow rate was 1.5 ml / min. The volume of the test sample was 40 μl with a solution concentration of 0.25 mg / ml (the original substance of ibrutinib) and 0.30 mg / ml (a new, previously unknown, μ - modification of ibrutinib). It turned out that the chromatograms of the starting substance ibrutinib, which was used as the starting material, and the new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H- Pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one contains one peak of the main component. The values of the retention times, within the limits of the determination error, are almost the same. The purity of the studied samples determined by HPLC was 99.84% (starting material) and 99.70% (new, previously unknown, crystalline μ - modification of ibrutinib).

The experiments performed by HPLC indicate that upon receipt of a new 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 from the starting material — crystalline modification of ibrutinib — Form A; no decomposition of the starting material.

Thus, the experimental results of nuclear magnetic resonance (NMR- ¹ H) and high performance liquid chromatography (HPLC) clearly indicate that the resulting substance is 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl ) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one.

To confirm that the obtained substance is a new, previously unknown 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, X-ray phase analysis (XRD) and thermal analyzes were performed.

). Полученные данные РФА для ибрутиниба, который использовали в качестве исходного вещества, приведены в табл. 2 и на рис. 3. Сравнение результатов РФА, представленных в табл. 2 и в табл. 1 (литературные данные), свидетельствует о том, что в качестве исходного вещества была использована известная кристаллическая модификация ибрутиниба - форма А. Результаты рентгенофазового анализа порошка, полученного из известной кристаллической модификации ибрутиниба, представлены в табл. 3 и на рис. 4. Сравнение полученных данных, представленных в табл. 3, табл. 2 и табл. 1, а также на рис. 3, рис. 4, и на рисунках, приведенных в литературных источниках (WO 2013/184572 А1 от 12.12.2013 г.; WO 2016/139588 А1 от 9.09.2016 г.; CN 105646484 А от 8.06.2016 г.; CN 105646498 А от 8.06.2016 г.; CN 105646499 А от 8.06.2016 г.; WO 2016/025720 А1 от 18.02.2016 г.; WO 2017/029586 А1 от 23.02.2017 г.; WO 2015/081180 А1 от 4.06.2015 г.; CN 104327085 А от 8.06.2016 г.; CN 105294696 А от 3.02.2016 г.; CN 106117214 А от 16.11.2016 г.; WO 2015/145415 А1 от 4.06.2015 г.; ЕР 3243824 А1 от 15.11.2017 г. и др.), свидетельствует о том, что полученный порошок ибрутиниба является новой, не известной ранее, кристаллической μ - модификацией 1-[(3R)-3-[4-амино-3-(4-феноксифенил)-1H-пиразоло[3,4-d]пиримидин-1-ил]-1-пиперидил]-2-пропенил-1-он.X-ray phase analysis of the known crystalline modification of ibrutinib form A, which was used as the starting material and the substance obtained from it, was carried out on a Rigaku D / MAX-2500 diffractometer (Rigaku, Japan) using CuKα radiation (λ = 1.54056

) The obtained XRD data for ibrutinib, which was used as the starting material, are given in table. 2 and in fig. 3. Comparison of the results of the XRD shown in table. 2 and in table. 1 (literature data), indicates that the known crystalline modification of ibrutinib - Form A was used as the starting material. The results of X-ray phase analysis of the powder obtained from the known crystalline modification of ibrutinib are presented in Table. 3 and in fig. 4. Comparison of the data presented in table. 3, tab. 2 and tab. 1, as well as in fig. 3, fig. 4 and in the figures given in the literature (WO 2013/184572 A1 dated 12.12.2013; WO 2016/139588 A1 dated 09/09/2016; CN 105646484 A dated 06/08/2016; CN 105646498 A dated 8.06 .2016; CN 105646499 A dated June 8, 2016; WO 2016/025720 A1 dated February 18, 2016; WO 2017/029586 A1 dated February 23, 2017; WO 2015/081180 A1 dated June 4, 2015. ; CN 104327085 A dated 06/08/2016; CN 105294696 A dated 02/03/2016; CN 106117214 A dated 11.16.2016; WO 2015/145415 A1 dated 06/04/2015; EP 3243824 A1 dated 11/15/2017 G. and others), indicates that the obtained ibrutinib powder is a new, previously unknown, 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.

) и соответствующих им интенсивностей (I_отн., %): 15,477

- 42,64%; 11,171

- 19,92%; 9,896

- 17,53%; 8,207

- 35,06%; 7,137

- 28,61%; 6,716

- 27,49%; 6,433

- 39,13%; 6,200

- 36,19%; 5,849

- 35,62%; 5,641

- 43,20%; 5,516

- 43,90%; 5,268

- 46,14%; 5,053

- 49,65%; 4,845

- 59,61%; 4,667

- 70,13%; 4,581

- 63,67%; 4,454

- 69,57%; 4,316

- 59,61%; 4,267

- 57,22%; 4,152

- 100,00%; 4,084

- 73,07%; 3,955

- 53,16%; 3,920

- 50,91%; 3,863

- 47,41%; 3,776

- 52,59%; 3,732

- 39,69%; 3,627

- 35,62%; 3,578

- 39,13%; 3,536

- 34,50%; 3,476

- 35,62%; 3,350

- 43,20%; 3,259

- 31,00%; 3,137

- 29,87%; 3,082

- 32,12%; 2,983

- 25,67%; 2,937

- 25,11%; 2,825

- 22,16%; 2,768

- 19,35%; 2,708

- 20,48%; 2,610

- 16,97%; 2,571

- 15,85%; 2,482

- 16,41%; 2,387

- 17,53%; 2,379

- 16,97%; 2,295

-17,53%; 2,240

- 14,59%; 2,162

- 14,59%.Thus, the experimental results of x-ray phase analysis clearly indicate that the obtained substance is a new, previously unknown, 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. It is characterized by a combination of interplanar distances (d,

) and their corresponding intensities (I _rel. ,%): 15,477

- 42.64%; 11,171

- 19.92%; 9,896

- 17.53%; 8,207

- 35.06%; 7,137

- 28.61%; 6,716

- 27.49%; 6,433

- 39.13%; 6,200

- 36.19%; 5,849

- 35.62%; 5,641

- 43.20%; 5,516

- 43.90%; 5,268

- 46.14%; 5,053

- 49.65%; 4,845

- 59.61%; 4,667

- 70.13%; 4,581

- 63.67%; 4,454

- 69.57%; 4,316

- 59.61%; 4,267

- 57.22%; 4,152

- 100.00%; 4,084

- 73.07%; 3,955

- 53.16%; 3,920

- 50.91%; 3,863

- 47.41%; 3,776

- 52.59%; 3,732

- 39.69%; 3,627

- 35.62%; 3,578

- 39.13%; 3,536

- 34.50%; 3,476

- 35.62%; 3,350

- 43.20%; 3,259

- 31.00%; 3,137

- 29.87%; 3,082

- 32.12%; 2,983

- 25.67%; 2,937

- 25.11%; 2,825

- 22.16%; 2,768

- 19.35%; 2,708

- 20.48%; 2,610

- 16.97%; 2,571

- 15.85%; 2,482

- 16.41%; 2,387

- 17.53%; 2,379

- 16.97%; 2,295

-17.53%; 2,240

- 14.59%; 2,162

- 14.59%.

Thermoanalytical studies were performed on a DSC 204 F1 Poenix (NETZSCH) and DSC Q 100 TA Instruments thermal analyzer in an argon flow at a temperature increase of 10 deg / min. Aluminum cuvettes were used as sample holders. The sample weight was 1.2-5.2 mg. It turned out that the melting point of the starting substance ibrutinib, which was used as the starting material, is 154.2-158.2 ° C (endothermic effect on the DSC curve). This temperature (154-157) ° C is characteristic of crystalline form A of ibrutinib known from the literature (WO 2013/184572 A1 of 12.12.2013). The melting point of a new, previously unknown crystalline μ is modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one is 142.3-151.5 ° C (endothermic effect on the DSC curve). A comparison of this temperature with the temperatures of thermal effects and the melting points of crystalline modifications known from the literature (Table 4) shows that a new, previously unknown, crystalline μ - modification 1 - [(3R) -3- [4-amino-3- ( 4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one is characterized by a melting point different from other modifications of ibrutinib (142.3- 151.5) ° С (endothermic effect on the DSC curve).

The experimental data presented for x-ray phase analysis and thermoanalytical studies clearly indicate that the obtained new, previously unknown, crystalline μ is a 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 characterized by a combination of interplanar distances and their corresponding intensities and a melting point (different from other crystalline modifications of ibrutinib) and the melting temperature (endothermic effect on DSC - curve).

A method of obtaining a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, consists in the fact that a solution of ibrutinib in an organic solvent at 25-80 ° C is mixed with water in a ratio of 1: 2-1: 4, frozen at a cooling rate not lower than 60 deg / min, is freeze-dried and further annealed at temperatures (90-110) ° C for (0.5-5.0) hours.

The difference in the method of obtaining the inventive new, previously unknown, crystalline μ - modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1- il] -1-piperidyl] -2-propenyl-1-one from the method for producing known crystalline forms of ibrutinib is that a solution of ibrutinib in an organic solvent at 25-80 ° C is mixed with water in a ratio of 1: 2-1: 4, they are frozen at a cooling rate not lower than 60 deg / min, freeze-dried and further annealed at temperatures (90-110) ° С for (0.5-5.0) hours.

The proposed method of obtaining, which consists in the fact that a solution of ibrutinib in an organic solvent at 25-80 ° C is mixed with water in a ratio of 1: 2-1: 4, frozen at a cooling rate of at least 60 deg / min, subjected to freeze-drying and additionally annealed at temperatures of (90-110) ° C for (0.5-5.0) hours, allows you to get a new, previously unknown, crystalline μ - modification 1 - [(3R) -3- [4-amino-3 - (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one.

The preparation of ibrutinib solution at elevated temperatures was used to accelerate the dissolution process.

Reducing the temperature of the solution of ibrutinib in an organic solvent below 25 ° C is not advisable since it requires additional energy for cooling the system.

An increase in the temperature of the solution of ibrutinib in an organic solvent above 80 ° C is also not advisable because of the need to use special equipment.

Mixing an organic solution of ibrutinib in an organic solvent with water in a ratio of less than 1: 2 leads to the formation of one of the known modifications of ibrutinib under these conditions. To obtain a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one in its pure form fails.

Mixing an organic solution of ibrutinib in an organic solvent with water in a ratio of more than 1: 4 does not increase the yield of the target product, a new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- ( 4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one and only increases the cost of production.

A decrease in the freezing rate below 60 deg / min leads to the fact that the cryocrystallization rate of the ibrutinib solution decreases and approaches the equilibrium process. This leads to the already known modifications. To obtain a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one in its pure form fails. Note that the known method of freezing a solution containing ibrutinib (WO 2016/079216 A1 dated 05/26/2016) involves freezing on a shelf a sublimation unit at -30 ° C. Under these conditions, as a rule, the freezing speed reaches not more than (20-30) deg / min.

Freeze-drying of a frozen solution of ibrutinib is necessary to obtain a dry powder, which subsequently allows the formation of a completely new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H -pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one. The preferred mode of freeze-drying is a process that is carried out at temperatures: on the condenser -43 ° C ... -56 ° C; on the product -196 ... + 50 ° C and a residual pressure in the chamber (9-3) × 10 ^-2 Torr for 22-26 hours

Reducing the freeze-drying time of less than 22 hours results in a non-dried product: "ibrutinib powder - its frozen solution." The system melts at room temperature, the powder partially dissolves, recrystallizes, forming known modifications. A new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1 -piperidyl] -2-propenyl-1-one in its pure form can not be obtained.

An increase in the freeze-drying time of more than 26 hours is impractical, since it does not increase the yield of the target product — a new, previously unknown 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 and only increases the cost of production.

Additional annealing of freeze-drying products at temperatures of (90-110) ° C for (0.5-5.0) hours allows one to obtain a completely new, previously unknown, crystalline μ - modification 1 - [(3R) -3- [4 -amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one.

A decrease in the temperature of additional annealing of freeze-drying products below 90 ° C leads to the fact that under these conditions one of the known modifications of ibrutinib is formed. To obtain a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one in its pure form fails.

An increase in the temperature of additional annealing of freeze-drying products above 110 ° C leads to the fact that under these conditions one of the known modifications of ibrutinib is formed. To obtain a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one in its pure form fails.

Exposure of freeze-drying products at temperatures of 90-110 ° C for less than 0.5 hours leads to the formation of one of the known modifications of ibrutinib under these conditions. To obtain a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one in its pure form fails.

The possibility of carrying out the invention is illustrated by the following examples, but is not limited to.

Example 1. 50 ml of 5.00 wt. % solution of ibrutinib in an organic solvent - dimethyl sulfoxide (DMSO), prepared from the well-known crystalline modification of ibrutinib - form A, and dimethyl sulfoxide of the grade "ХЧ" ТУ 6-09-3818-77 manufactured by LLC NPP Viking, RF, at 80 ° С, mixed with 200 ml of purified water according to FS 42-2619-97 (ratio 1: 4) and frozen at a rate of 60 deg./min by pouring immediately the entire volume of the solution into a pre-filled with liquid nitrogen (T _boil = -196 ° C), but not pre-cooled, stainless steel tray. The frozen product on a pallet is transferred to a freeze-drying chamber and freeze-dried at temperatures: -43 ° С ... -46 ° С on a condenser; on the product -196 ° С ... + 50 ° С and a residual pressure in the chamber (8-6) ⋅10 ^-2 Torr for 22 hours. The product of freeze-drying is a light, fluffy white powder, placed in a 400 ml chemical heat-resistant glass , bring it into a drying cabinet preheated to 90 ° C and maintain at this temperature for 5.0 hours. The yield of light product, white powder was 2.30 g (92.0 wt.%). According to the XRD data, the obtained substance is characterized by a typical diffractogram shown in Fig. 4 and a set of interplanar distances and their intensities coinciding with the corresponding values for the new, previously unknown, crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [ 3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, are presented in table. 3. According to thermoanalytical studies, the obtained substance is characterized by a melting point equal to 142.3-151.5 ° C and coinciding, within the limits of the determination error, with the corresponding values for a new, previously unknown, crystalline μ - modification 1 - [(3R) - 3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one. According to HPLC, the purity of the obtained new, previously unknown, crystalline μ - modification of ibrutinib is 99.67%.

Example 2. 100 ml of 2.00 wt. % solution of ibrutinib in an organic solvent - methanol, prepared from the well-known crystalline modification of ibrutinib - form A, and methyl alcohol of the grade "ХЧ" GOST 2222-95 of the company "Vecton-M" LLC, RF, at 50 ° С, mixed with 200 ml of water purified according to GF XIII FS 2.2.0020.15 FS (1: 2 ratio) and frozen at a rate of (2-3) × 10 ² deg / min by pouring the solution in small portions into pre-cooled and filled with liquid nitrogen (T _bp = -196 ° С) stainless steel tray. The frozen product on a pallet is transferred to a freeze-drying chamber and subjected to freeze-drying at temperatures: on a condenser -52 ° С ... -56 ° С; on the product -196 ° С ... + 30 ° С and a residual pressure in the chamber (9-5) ⋅10 ^-2 Torr for 26 hours. The product of freeze-drying is a light, fluffy white powder, placed in a 400 ml chemical heat-resistant glass , bring it into a drying cabinet preheated to 110 ° C and maintain at this temperature for 0.5 hours. The yield of light product, white powder was 1.88 g (94.0 wt.%). According to X-ray powder diffraction data, the obtained substance is characterized by a typical diffractogram shown in Fig. 4 and a set of interplanar distances and their intensities coinciding with the corresponding values for a new, previously unknown, 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, are presented in table. 3. According to the data of thermoanalytical studies, the obtained substance is characterized by a melting point equal to (141.8-151.7) ° С and coinciding, within the limits of the determination error, with the corresponding values for a new crystalline μ - modification 1 - [(3R ) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one. According to HPLC, the purity of the obtained new, previously unknown, crystalline μ - modification of ibrutinib is 99.72%.

Example 3. 50 ml of 0.30 wt. % solution of ibrutinib in an organic solvent - acetonitrile, prepared from the well-known crystalline modification of ibrutinib - form A, and acetonitrile grade "ХЧ" TU 6-094326-76 of the company "Component - Reagent LLC, RF", at 25 ° C, mixed with 150 ml water purified according to GF XIII FS 2.2.0020.15 (ratio 1: 3) and frozen at a speed of about 10 deg / min by spraying the solution with a pneumatic nozzle at an overpressure of 0.6 kg / cm ² into a reactor filled with liquid nitrogen (T _boil = -196 ° C). The frozen solution, in the form of microgranules, is transferred to a stainless steel tray and subjected to freeze-drying at temperatures: on a condenser -48 ° С ... -54 ° С; on the product -196 ° С ... + 40 ° С, and a residual pressure in the chamber (6-3) ⋅10 ^-2 Torr for 24 hours. The freeze-drying product is a light, fluffy white powder, placed in a heat-resistant chemical glass with a capacity of 200 ml, bring it into a drying cabinet preheated to 100 ° C and maintain at this temperature for 3.0 hours. The yield of light product, an almost white powder, was 0.14 g (93.0 wt.%). According to the XRD data, the obtained substance is characterized by a typical diffractogram shown in Fig. 4 and a set of interplanar distances and their intensities coinciding with the corresponding values for the new, previously unknown, crystalline μ - modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [ 3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, are presented in table. 3. According to thermoanalytical studies, the obtained substance is characterized by a melting point equal to (142.7-151.2) ° С and coinciding, within the limits of the determination error, with the corresponding values for a new, previously unknown, crystalline μ - modification 1 - [(3R ) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one. According to HPLC, the purity of the obtained new, previously unknown, crystalline μ - modification of ibrutinib is 99.70%.

Example 4. To a solution of 0.5 kg (1.2939 mol) (3R) -4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine synthesized by a known method [application WO 2017/039425], in 11 l of dichloromethane, 144 g (1.4232 mol) of triethylamine are added with stirring. The resulting solution was cooled to 0 ° C, and 123 g (1.3586 mol) of acryloyl chloride was added to it over 30 minutes, maintaining the temperature of the reaction mixture not higher than + 10 ° C. Next, the reaction mixture was stirred at 20 ° C for another 2 hours, after which it was transferred to a separation tank and washed first with 2 times of 6 L of a 5% aqueous solution of citric acid, and then with 10 L of concentrated brine. The organic phase is separated off, dichloromethane is distilled off in vacuo, dry toluene (12 L) is added to the residue. The toluene solution is evaporated under vacuum to half the volume, while the residual water is removed in the form of an azeotrope with toluene. The remaining toluene solution containing the product is brought to a boil at atmospheric pressure, and then gradually cooled to a temperature of 45 ° C over an hour. The resulting solution was seeded with 0.2 g of the μ-form of ibrutinib obtained in the previous examples, and kept at room temperature with slow stirring for 14 hours. The resulting precipitate was filtered off, washed on the filter with dry heptane (1 L) and dried under vacuum to constant mass. Obtain 524 g of the μ-crystalline form of ibrutinib. Yield 92%.

Example 5. The pharmaceutical composition. To prepare 5.00 g of the known composition, including as an active substance, the crystalline modification of ibrutinib and excipients in the ratio (wt.%):

Active substance: ibrutinib 42,42 Microcrystalline cellulose 45.88 Croscarmellose sodium 6.97 Sodium lauryl sulfate 4.24 Magnesium stearate 0.49

2.12 g of powder as a seed, 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 mixed for 15 minutes in a ceramic mortar with excipients: 2.29 g of microcrystalline cellulose (according to the US Pharmacopoeia and European Pharmacopoeia), 0.35 g of croscarmellose sodium (according to the pharmacopeia USA and European Pharmacopoeia), 0.21 g of sodium lauryl sulfate (according to the US Pharmacopoeia and European Pharmacopoeia) and 0.03 g of magnesium stearate (according to TU 6-09-16-1533-90). The resulting mixture was subjected to physico-chemical and biological methods of analysis. According to X-ray powder diffraction data, the mixture contains a substance that is characterized by a set of interplanar spacings and their intensities that coincide with the corresponding values for the new, previously unknown, crystalline μ - modification 1 - [(3R) -3- [4-amino-3- ( 4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, are shown in table. 3.

In a similar way and identical in composition, a composition was prepared on the basis of the known crystalline modification of ibrutinib - Form A, which was used as the starting material. According to the XRD data, a mixture is present in the resulting mixture that is characterized by a set of interplanar distances and their intensities that match the corresponding values for the known modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, are presented in table. 2.

Biological experiments were carried out on male rabbits weighing 2.0-2.5 kg. To obtain reliable results in a parallel series of experiments used at least 5 rabbits. The time of appearance of ibrutinib in the blood was determined by the in vivo method with the oral administration of the composition, followed by the collection of plasma from the vein of the auricle. In all cases, the amount of the prepared mixture introduced into the animal was 11.79 mg of the mixture (5.00 mg of ibrutinib). It turned out that for a composition containing a new, previously unknown, crystalline μ - modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine -1-yl] -1-piperidyl] -2-propenyl-1-one the appearance time of the drug in the blood of rabbits is 14 ± 3 min, and for the known composition containing the known crystalline modification of ibrutinib (form A) as the active substance, 26 ± 3 minutes

Thus, we discovered a new, previously unknown, 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, a method for its preparation and its use for the preparation of a pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase inhibitor for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia are proposed.

) и соответствующих им интенсивностей (I_отн., %): 15,477

- 42,64%; 11,171

- 19,92%; 9,896

- 17,53%; 8,207

- 35,06%; 7,137

- 28,61%; 6,716

- 27,49%; 6,433

- 39,13%; 6,200

- 36,19%; 5,849

- 35,62%; 5,641

- 43,20%; 5,516

- 43,90%; 5,268

- 46,14%; 5,053

- 49,65%; 4,845

- 59,61%; 4,667

- 70,13%; 4,581

- 63,67%; 4,454

- 69,57%; 4,316

- 59,61%; 4,267

- 57,22%; 4,152

- 100,00%; 4,084

- 73,07%; 3,955

- 53,16%; 3,920

- 50,91%; 3,863

- 47,41%; 3,776

- 52,59%; 3,732

- 39,69%; 3,627

- 35,62%; 3,578

- 39,13%; 3,536

- 34,50%; 3,476

- 35,62%; 3,350

- 43,20%; 3,259

- 31,00%; 3,137

- 29,87%; 3,082

- 32,12%; 2,983

- 25,67%; 2,937

- 25,11%; 2,825

- 22,16%; 2,768

- 19,35%; 2,708

- 20,48%; 2,610

- 16,97%; 2,571

- 15,85%; 2,482

- 16,41%; 2,387

- 17,53%; 2,379

- 16,97%; 2,295

- 17,53%; 2,240

- 14,59%; 2,162

- 14,59%.The obtained new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one is characterized by a set of interplanar distances different from the known crystalline modifications of ibrutinib (d,

) and their corresponding intensities (I _rel. ,%): 15,477

- 42.64%; 11,171

- 19.92%; 9,896

- 17.53%; 8,207

- 35.06%; 7,137

- 28.61%; 6,716

- 27.49%; 6,433

- 39.13%; 6,200

- 36.19%; 5,849

- 35.62%; 5,641

- 43.20%; 5,516

- 43.90%; 5,268

- 46.14%; 5,053

- 49.65%; 4,845

- 59.61%; 4,667

- 70.13%; 4,581

- 63.67%; 4,454

- 69.57%; 4,316

- 59.61%; 4,267

- 57.22%; 4,152

- 100.00%; 4,084

- 73.07%; 3,955

- 53.16%; 3,920

- 50.91%; 3,863

- 47.41%; 3,776

- 52.59%; 3,732

- 39.69%; 3,627

- 35.62%; 3,578

- 39.13%; 3,536

- 34.50%; 3,476

- 35.62%; 3,350

- 43.20%; 3,259

- 31.00%; 3,137

- 29.87%; 3,082

- 32.12%; 2,983

- 25.67%; 2,937

- 25.11%; 2,825

- 22.16%; 2,768

- 19.35%; 2,708

- 20.48%; 2,610

- 16.97%; 2,571

- 15.85%; 2,482

- 16.41%; 2,387

- 17.53%; 2,379

- 16.97%; 2,295

- 17.53%; 2,240

- 14.59%; 2,162

- 14.59%.

In addition, a new, previously unknown crystalline μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl ] -1-piperidyl] -2-propenyl-1-one is characterized by increased biological activity in the pharmaceutical composition compared with the known crystalline modification of ibrutinib (Form A), which was used as the starting material.

From the foregoing, we can conclude that the claimed new, previously unknown, crystalline μ is a modification of 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4- d] pyrimidin-1-yl] -1-piperidyl] -2-propenyl-1-one, the method for its preparation and its use for preparing the pharmaceutical composition as a covalent selective Bruton tyrosine kinase inhibitor for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia are new and satisfy the criteria of "inventive step" and "industrial applicability".

[1] - WO 2013/184572 A1 of 12.12.2013; [2] - WO 2016/139588 A1 of 09/09/2016; [3] - CN 105646484 A dated 06/08/2016; [4] - CN 105646498 A dated 06/08/2016; [5] - CN 105646499 A dated 06/08/2016; [6] - WO 2016/025720 A1 dated February 18, 2016.

[7] - WO 2017/029586 A1 of February 23, 2017

[8] - WO 2015/081180 A1 of June 4, 2015; [9] - CN 104327085 A dated 06/08/2016; [10] - CN 105294696 A dated February 3, 2016; [11] - CN 106117214 A dated 11.16.2016.

[12] - WO 2015/145415 A2 of October 1, 2015; [13] - EP 3243824 Al dated 11/14/2017

[13] - EP 3243824 A1 of 11/14/2017

Claims (5)

1. 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, characterized by the following set of interplanar spacings (d,

) and their corresponding intensities (I _rel. ,%): 15,477

- 42.64%; 11,171

- 19.92%; 9,896

- 17.53%; 8,207

- 35.06%; 7,137

- 28.61%; 6,716

- 27.49%; 6,433

- 39.13%; 6,200

- 36.19%; 5,849

- 35.62%; 5,641

- 43.20%; 5,516

- 43.90%; 5,268

- 46.14%; 5,053

- 49.65%; 4,845

- 59.61%; 4,667

- 70.13%; 4,581

- 63.67%; 4,454

- 69.57%; 4,316

- 59.61%; 4,267

- 57.22%; 4,152

- 100.00%; 4,084

- 73.07%; 3,955

- 53.16%; 3,920

- 50.91%; 3,863

- 47.41%; 3,776

- 52.59%; 3,732

- 39.69%; 3,627

- 35.62%; 3,578

- 39.13%; 3,536

- 34.50%; 3,476

- 35.62%; 3,350

- 43.20%; 3,259

- 31.00%; 3,137

- 29.87%; 3,082

- 32.12%; 2,983

- 25.67%; 2,937

- 25.11%; 2,825

- 22.16%; 2,768

- 19.35%; 2,708

- 20.48%; 2,610

- 16.97%; 2,571

- 15.85%; 2,482

- 16.41%; 2,387

- 17.53%; 2,379

- 16.97%; 2,295

- 17.53%; 2,240

- 14.59%; 2,162

- 14.59%. 2. The method of obtaining crystalline μ-modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl ] -2-propenyl-1-one according to claim 1, characterized in that the solution of ibrutinib in an organic solvent at 25-80 ° C is mixed with water in a ratio of 1: 2-1: 4, frozen at a cooling rate of at least 60 degrees / min, subjected to freeze-drying and additionally annealed at a temperature of (90-110) ° C for (0.5-5.0) hours. 3. The method according to p. 2, characterized in that the freeze-drying of a frozen solution of ibrutinib is carried out at temperatures: on a condenser (-43 ... -56) ° C; on the product (-196 ... + 50) ° С and the residual pressure in the chamber (9-3) × 10 ^-2 Torr for 22-26 hours 4. The method of obtaining crystalline μ-modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl ] -2-propenyl-1-one according to claim 1, carried out by the interaction of (3R) -4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine with acryloyl chloride, characterized in that at the crystallization stage of the product, a seed of a small amount of μ modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] - 1-piperidyl] -2-propenyl-1-one. 5. The use of crystalline μ-modification 1 - [(3R) -3- [4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -1-piperidyl] The -2-propenyl-1-one according to claim 1 for the preparation of a pharmaceutical composition as a covalent selective inhibitor of Bruton tyrosine kinase for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia.

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